Crystalline ppar-delta agonist

ABSTRACT

Described herein is crystalline sodium (E)-2-(4-((3-(4-fluorophenyl)-3-(4-(3-morpholinoprop-1-yn-1-yl)phenyl)allyl)oxy)-2-methylphenoxy)acetate, uses of such crystalline material in the preparation of pharmaceutical compositions for the treatment of diseases or conditions that would benefit by administration with a PPARS agonist compound.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.17/572,037, filed Jan. 10, 2022, which is continuation of U.S.application Ser. No. 17/381,005, filed Jul. 20, 2021, now issued as U.S.Pat. No. 11,267,795 issued on Mar. 8, 2022, which claims the benefit ofU.S. Provisional Application No. 63/118,431, filed Nov. 25, 2020, andU.S. Provisional Application No. 63/055,235, filed Jul. 22, 2020, eachof which is incorporated herein by reference in its entirety.

FIELD OF THE INVENTION

Described herein are crystalline forms of a peroxisomeproliferator-activated receptor delta (PPARδ) agonist compound, as wellas pharmaceutical compositions thereof, and methods of use thereof inthe treatment of diseases or conditions that would benefit fromtreatment with a PPARδ agonist compound.

BACKGROUND OF THE INVENTION

PPARδ, a member of the nuclear regulatory superfamily ofligand-activating transcriptional regulators, is expressed throughoutthe body. PPARδ agonists induce genes related to fatty acid oxidationand mitochondrial biogenesis. PPARδ also has anti-inflammatoryproperties.

SUMMARY OF THE INVENTION

The present disclosure relates to various solid state forms of the PPARδagonist sodium(E)-2-(4-((3-(4-fluorophenyl)-3-(4-(3-morpholinoprop-1-yn-1-yl)phenyl)allyl)oxy)-2-methylphenoxy)acetate.Such forms of sodium(E)-2-(4-((3-(4-fluorophenyl)-3-(4-(3-morpholinoprop-1-yn-1-yl)phenyl)allyl)oxy)-2-methylphenoxy)acetateare useful for modulating the activity PPARδ in mammals that wouldbenefit from such activity.

Described herein is crystalline sodium(E)-2-(4-((3-(4-fluorophenyl)-3-(4-(3-morpholinoprop-1-yn-1-yl)phenyl)allyl)oxy)-2-methylphenoxy)acetate(Compound II).

In some embodiments, Compound II is crystalline Form 1. In someembodiments, crystalline Form 1 is characterized as having:

-   -   (a) an XRPD pattern substantially the same as shown in FIG. 1 ;    -   (b) an XRPD pattern with peaks at about 2.8° 2-Theta, about 7.2°        2-Theta, about 13.4° 2-Theta, about 17.8° 2-Theta, about 19.7°        2-Theta, about 19.9° 2-Theta, and about 20.6° 2-Theta as        measured using Cu Kα radiation;    -   (c) a DSC thermogram substantially the same as shown in FIG. 2 ;    -   (d) a DSC thermogram with an endotherm having onset at about        179.5° C. and peak at about 181.6° C.;    -   (e) a TGA pattern substantially the same as shown in FIG. 3 ;    -   (f) a TGA pattern with a 0.1% w/w loss from 25 to 60° C. and        degradation onset at about 250° C.;    -   (g) an FTIR spectroscopy pattern substantially the same as shown        in FIG. 4 ;    -   (h) an FTIR spectroscopy pattern with peaks at about 103 cm⁻¹,        about 838 cm⁻¹, about 1220 cm⁻¹, about 1504 cm⁻¹, and about 1612        cm⁻¹;    -   (i) a Raman spectroscopy pattern substantially the same as shown        in FIG. 5 ;    -   (j) a Raman spectroscopy pattern with peaks at about 103 cm⁻¹,        about 126 cm⁻¹, about 810 cm⁻¹, about 1158 cm⁻¹, about 1238        cm⁻¹, about 1604 cm⁻¹, and about 1629 cm⁻¹;    -   (k) unit cell parameters substantially equal to the following at        100 K:

Crystal System Monoclinic Space Group P2/c a (Å) 31.581(3) b (Å)6.1180(4) c (Å) 27.2046(18) α ° 90 β ° 94.447(7) γ ° 90 V (Å³) 5240.4(7)Z 8 Calculated Density (Mg/m³) 1.363 Absorption coefficient (mm⁻¹) 0.937F(000) 2256or

-   -   (l) combinations thereof.

In some embodiments, the crystalline Compound II is unsolvated.

In some embodiments, the crystalline Compound II is a solvate. In someembodiments, crystalline compound II is an acetone solvate, 1-propanolsolvate, 2-methyltetrahydrofuran solvate, methyl isobutyl ketonesolvate, 1,4-dioxane solvate, chloroform solvate, tetrahydrofuransolvate, or dichloromethane solvate.

In some embodiments, the crystalline Compound II is a hydrate. In someembodiments described herein, the crystalline hydrate is crystallineForm 2 of Compound II. In some embodiments, crystalline Form 2 ofCompound II is characterized as having:

-   -   (a) an XRPD pattern substantially the same as shown in FIG. 6 ;    -   (b) an XRPD pattern with peaks at about 4.5 2-Theta, about 13.8°        2-Theta, about 17.6° 2-Theta, about 19.0° 2-Theta, about 19.6°        2-Theta, about 19.9° 2-Theta, about 20.5° 2-Theta, and about        23.0° 2-Theta as measured using Cu Kα radiation;    -   (c) a DSC thermogram substantially the same as shown in FIG. 7 ;    -   (d) a DSC thermogram with six endothermic events having:        -   i. an onset at about 44.1° C. and a peak at about 72.4° C.;        -   ii. a peak at about 92.4° C.;        -   iii. an onset at about 107.0° C. and a peak at about 118.5°            C.;        -   iv. an onset at about 127.6° C. and a peak at about 130.0°            C.;        -   v. an onset at about 146.9° C. and a peak at about 149.9°            C.; and        -   vi. an onset at about 179.5° C. and a peak at about 181.1°            C.;    -   (e) a TGA pattern substantially the same as shown in FIG. 8 ;    -   (f) a TGA pattern with a 17.2% w/w loss from 25 to 145° C., and        degradation onset at about 275° C.;    -   (g) reversible water uptake (˜25% w/w) between 0 and 90%        Relative Humidity (RH);    -   (h) an unchanged XRPD after GVS analysis at 90% RH and 25° C.;    -   (i) an unchanged XRPD after storage at 97% RH and 25° C. over 7        days;    -   (j) an unchanged XRPD after storage at 75% RH and 40° C. over 7        days; or    -   (k) combinations thereof.

In some embodiments, the crystalline Compound II is a2-methyltetrahydrofuran solvate. In some embodiments described herein,the crystalline 2-methyltetrahydrofuran solvate is crystalline Form 3 ofCompound II. In some embodiments, crystalline Form 3 of Compound II ischaracterized as having:

-   -   (a) an XRPD pattern substantially the same as shown in FIG. 9 ;    -   (b) a DSC thermogram substantially the same as shown in FIG. 10        ;    -   (c) a DSC thermogram with three endothermic events having:        -   i. an onset at about 58.7° C. and a peak at about 73.2° C.;        -   ii. an onset at about 114.5° C. and a peak at about 136.2°            C.; and        -   iii. an onset at about 172.5° C. and a peak at about 178.6°            C.;    -   (d) a TGA pattern substantially the same as shown in FIG. 11 ;    -   (e) a TGA pattern with a 2.3% w/w loss from 25 to 82° C., a        further 3.8% w/w loss from 82° C. to 155° C., and a degradation        onset at about 275° C.;    -   (f) reversible water uptake (˜9.0% w/w) between 0 and 90%        Relative Humidity (RH);    -   (g) an XRPD that converts to Form 1 after GVS analysis at 90% RH        and 25° C.;    -   (h) an XRPD that converts to Form 1 after storage at 75% RH and        40° C. for 7 days; or    -   (i) combinations thereof.

In some embodiments, the crystalline Compound II is a tetrahydrofuransolvate. In some embodiments described herein, the crystallinetetrahydrofuran solvate is crystalline Form 4 of Compound II. In someembodiments, crystalline Form 4 of Compound II is characterized ashaving:

-   -   (a) an XRPD pattern substantially the same as shown in FIG. 12 ;    -   (b) an XRPD pattern with peaks at about 3.3° 2-Theta, about 6.7°        2-Theta, about 20.1° 2-Theta, and about 20.7° 2-Theta as        measured using Cu Kα radiation;    -   (c) a DSC thermogram substantially the same as shown in FIG. 13        ;    -   (d) a DSC thermogram with two endothermic events having:        -   i. an onset at about 111.7° C. and a peak at about 114.5° C.            with a broad shoulder starting at about 70° C.; and        -   ii. an onset at about 142.5° C. and a peak at about            147.2° C. with a broad shoulder starting at about 130.6° C.;    -   (e) a TGA pattern substantially the same as shown in FIG. 14 ;    -   (f) a TGA pattern with a 14.3% w/w loss from 25 to 175° C., and        degradation onset at about 285° C.;    -   (g) reversible water uptake (˜23% w/w) between 0 and 90%        Relative Humidity (RH);    -   (h) an XRPD that converts to Form 2 after GVS analysis at 90% RH        and 25° C.;    -   (i) an unchanged XRPD after heating to 110° C.;    -   (j) an XRPD that converts to Form 2 after storage at 97% RH and        25° C. over 7 days;    -   (k) an XRPD that converts to Form 1 after storage at 75% RH and        40° C. over 7 days; or    -   (l) combinations thereof.

In some embodiments, the crystalline Compound II is an acetone solvate.In some embodiments described herein, the crystalline acetone solvate iscrystalline Form 5 of Compound II. In some embodiments, crystalline Form5 of Compound II is characterized as having:

-   -   (a) an XRPD pattern substantially the same as shown in FIG. 15 ;    -   (b) an XRPD pattern with peaks at about 2.8 2-Theta, about 8.3°        2-Theta, about 8.7° 2-Theta, about 13.1° 2-Theta, about 19.4°        2-Theta, about 20.2° 2-Theta, about 21.3° 2-Theta, and about        24.6° 2-Theta as measured using Cu Kα radiation;    -   (c) a DSC thermogram substantially the same as shown in FIG. 16        ;    -   (d) a DSC thermogram with two endothermic events having:        -   i. an onset at 75.8° C. and two peaks at about 85.8° C. and            97.2° C.; and        -   ii. onset at 180.4° C. and a peak at 182.2;    -   (e) an FTIR spectroscopy pattern substantially the same as shown        in FIG. 17 ; or    -   (f) an FTIR spectroscopy pattern with peaks at about 810 cm⁻¹,        about 838 cm⁻¹, about 1220 cm⁻¹, about 1504 cm⁻¹, and about 1612        cm⁻¹; or    -   (g) combinations thereof.

In some embodiments, crystalline Form 5 of Compound II is furthercharacterized as having: an XRPD that converts to Form 1 after drying;an XRPD that converts to Form 1 after GVS analysis at 90% RH and 25° C.;or combinations thereof.

Also described herein, in some embodiments, is amorphous sodium(E)-2-(4-((3-(4-fluorophenyl)-3-(4-(3-morpholinoprop-1-yn-1-yl)phenyl)allyl)oxy)-2-methylphenoxy)acetate(Compound II). In some embodiments, amorphous Compound II ischaracterized as having:

-   -   (a) an XRPD pattern showing a lack of crystallinity;    -   (b) a DSC thermogram substantially the same as shown in FIG. 22        ;    -   (c) a DSC thermogram with:        -   i. a broad endotherm with onset at 43.1° C. and peak at            about 60.3° C.;        -   ii. a broad exotherm with onset at 107.0° C. and peak at            112.9° C.; and        -   iii. an endotherm with onset at 125.0° C. peak a 130.4° C.;    -   (d) a TGA pattern substantially the same as shown in FIG. 23 ;    -   (e) a TGA pattern with a 3.7% w/w loss from 25 to 150° C., and a        degradation onset at about 260° C.;    -   (f) an unchanged XRPD after storage at ambient temperature over        24 hours, 48 hours, 7 days, or days;    -   (g) an unchanged XRPD after storage at 75% RH and 40° C. over 10        days; or    -   (h) combinations thereof.

Also described herein, in some embodiments, is a pharmaceuticalcomposition comprising a crystalline form Compound II and at least onepharmaceutically acceptable excipient. In other embodiments, is apharmaceutical composition comprising amorphous Compound II and at leastone pharmaceutically acceptable excipient. In some embodiments, thepharmaceutical composition is formulated for administration to a mammalby oral administration. In some embodiments, the pharmaceuticalcomposition is formulated for administration to a mammal by oraladministration in the form of a tablet, a pill, a capsule, a suspension,or a solution. In some embodiments, the pharmaceutical composition is inthe form of a solid form pharmaceutical composition. In someembodiments, the pharmaceutical composition is in the form of a tablet,a pill, or a capsule.

Also described herein is a process for the preparation of sodium(E)-2-(4-((3-(4-fluorophenyl)-3-(4-(3-morpholinoprop-1-yn-1-yl)phenyl)allyl)oxy)-2-methylphenoxy)acetate(Compound II) comprising treating(E)-2-(4-((3-(4-fluorophenyl)-3-(4-(3-morpholinoprop-1-yn-1-yl)phenyl)allyl)oxy)-2-methylphenoxy)aceticacid (Compound I), or the alkyl ester of Compound I, or a salt thereof,with a sodium hydroxide solution in the presence of a suitable solventto provide Compound II. In some embodiments, the alkyl ester is a C₁-C₆alkyl ester. In some embodiments, the suitable solvent is water,methanol, ethanol, tetrahydrofuran, ethyl acetate, acetone,acetonitrile, or a combination thereof. In some embodiments, thepreparation of the Compound II comprises treating Compound I with asodium hydroxide solution in the presence of a suitable solvent, whereinthe suitable solvent is water, methanol, ethanol, tetrahydrofuran, ethylacetate, acetone, acetonitrile, or a combination thereof. In someembodiments, the preparation of the Compound II comprises treatingCompound I with a sodium hydroxide solution in the presence of asuitable solvent, wherein the suitable solvent is a combination ofacetone and acetonitrile. In some embodiments, Compound II isCrystalline Form 1 as described herein.

Articles of manufacture, which include packaging material, a compounddescribed herein, or a pharmaceutically acceptable salt thereof, withinthe packaging material, and a label that indicates that the compound orcomposition, or pharmaceutically acceptable salt, pharmaceuticallyactive metabolite, pharmaceutically acceptable prodrug, orpharmaceutically acceptable solvate thereof, is used for modulating theactivity of PPARS, or for the treatment, prevention or amelioration ofone or more symptoms of a disease or condition that would benefit frommodulation of PPARS activity, are provided.

Other objects, features and advantages of the compounds, methods andcompositions described herein will become apparent from the followingdetailed description. It should be understood, however, that thedetailed description and the specific examples, while indicatingspecific embodiments, are given by way of illustration only, sincevarious changes and modifications within the spirit and scope of theinstant disclosure will become apparent to those skilled in the art fromthis detailed description.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 illustrates a representative XRPD pattern for Form 1 of CompoundII.

FIG. 2 illustrates a representative DSC thermogram for Form 1 ofCompound II.

FIG. 3 illustrates a representative TGA thermogram for Form 1 ofCompound II.

FIG. 4 illustrates a representative FTIR spectrum for Form 1 of CompoundII.

FIG. 5 illustrates a representative Raman spectrum for Form 1 ofCompound II.

FIG. 6 illustrates a representative XRPD pattern for Form 2 of CompoundII.

FIG. 7 illustrates a representative DSC thermogram for Form 2 ofCompound II.

FIG. 8 illustrates a representative TGA thermogram for Form 2 ofCompound II.

FIG. 9 illustrates a representative XRPD pattern for Form 3 of CompoundII.

FIG. 10 illustrates a representative DSC thermogram for Form 3 ofCompound II.

FIG. 11 illustrates a representative TGA thermogram for Form 3 ofCompound II.

FIG. 12 illustrates a representative XRPD pattern for Form 4 of CompoundII.

FIG. 13 illustrates a representative DSC thermogram for Form 4 ofCompound II.

FIG. 14 illustrates a representative TGA thermogram for Form 4 ofCompound II.

FIG. 15 illustrates a representative XRPD pattern for Form 5 of CompoundII.

FIG. 16 illustrates a representative DSC thermogram for Form 5 ofCompound II.

FIG. 17 illustrates a representative FTIR spectrum for Form 5 ofCompound II.

FIG. 18 illustrates a representative XRPD pattern for Pattern 9 ofCompound II.

FIG. 19 illustrates a representative DSC thermogram for Pattern 9 ofCompound II.

FIG. 20 illustrates a representative TGA thermogram for Pattern 9 ofCompound II.

FIG. 21 illustrates a representative XRPD pattern for amorphous CompoundII.

FIG. 22 illustrates a representative DSC thermogram for amorphousCompound II.

FIG. 23 illustrates a representative TGA thermogram for amorphousCompound II.

FIG. 24 illustrates a representative XRPD pattern for Pattern 12 ofCompound II.

FIG. 25 illustrates a representative DSC thermogram for Pattern 12 ofCompound II.

FIG. 26 illustrates a simulated XRPD pattern for Form 1 of Compound II.

FIG. 27 illustrates the overlap of the simulated and experimental XRPDpatterns for Form 1 of Compound II.

DETAILED DESCRIPTION OF THE INVENTION

(E)-2-(4-((3-(4-Fluorophenyl)-3-(4-(3-morpholinoprop-1-yn-1-yl)phenyl)allyl)oxy)-2-methylphenoxy)aceticacid (Compound I) is a potent, selective and orally bioavailable PPARagonist. The PPARs are members of the nuclear receptor superfamily,which are ligand-modulated transcription factors that regulate geneexpression of many cellular processes. The three PPARs, α, γ, and δ, areactivated by lipids and are targets for current drug therapies forcomponents of the metabolic syndrome. PPARα, a target for the fibrateclass of triglyceride (TG)-lowering drugs, is primarily expressed inliver, where it upregulates genes involved in lipid oxidation in thefasted state. PPARγ is highly expressed in adipose tissue and regulatesadipogenesis and insulin sensitivity. Pioglitazone is a drug from thethiazolidinedione class that increase insulin sensitivity throughactivating PPARγ. Compound I exhibits a significantly greaterselectivity for PPARδ over PPARα and PPARγ (by 100-fold and 400-fold,respectively), and acts as a full agonist of PPAR and only a partialagonist for both PPARα and PPARγ.

PPARδ controls genes involved in cellular metabolic processes such asglucose homeostasis, fatty acid synthesis and storage, and fatty acidmobilization and metabolism. PPARδ is expressed in several metabolicallyactive tissues including liver, muscle, and fat. It is the most abundantPPAR isoform in skeletal muscle and has a higher expression in oxidativetype I muscle fibers compared with glycolytic type II muscle fibers. Anumber of different physiological and pathological factors are reportedto influence skeletal muscle PPARδ content. Both short term exercise andendurance training lead to increased PPARδ expression in human androdent skeletal muscle. There is currently no marketed drug availabletargeting PPARδ.

Both genetic overexpression and pharmacological activation of PPARδ inmouse muscles results in increased number of fibers with highmitochondrial content and improves fatty acid oxidation. Overexpressionof a constitutively active PPAR (VP16-PPARδ) in skeletal muscles oftransgenic mice pre-programs an increase in oxidative muscle fibers,enhancing running endurance in untrained adult mice (Wang, Y.-X., et al.(2004). Regulation of muscle fiber type and running endurance by PPARδ.PLoS Biol. 2, e294). The PPAR agonist, GW1516, in combination withexercise (for 4 weeks) synergistically induced fatigue-resistantoxidative muscle fibers and mitochondrial biogenesis in mice, andtherefore enhanced physical performance (Narkar, V. A., et al. (2008).AMPK and PPARS agonists are exercise mimetics. Cell 134, 405-415). Whenmice were treated with GW1516 for a longer time (8 weeks compared to 4weeks) a clear shift in energy substrate usage from glucose to fattyacid oxidation to a level similar to exercise training was observed,indicative of increased fatty acid metabolism (Fan, W., et al. (2017).PPARδ Promotes Running Endurance by Preserving Glucose. Cell Metab. 25,1186-1193.e4).

Compound I

Compound I is a PPARδ agonist that is useful in the methods of treatmentdescribed herein. In human cell lines expressing the three peroxisomeproliferator-activated receptor (PPAR) isotypes, Compound I is a potent(EC50<100 nM) and selective human PPARδ agonist (PPARα (EC50>10 μM) andPPARγ (EC50>10 μM)). Compound I is a full PPARδ agonist. Additionally,exposure human cells expressing the nuclear receptors RXR, FXR, LXRa orDUO has not resulted in activation of these nuclear receptors.

In vivo experiments demonstrated that Compound I treatment altered theexpression patterns of several well-known PPARδ regulated genes inpathways involved in the beta-oxidation of long chain fatty acids(CPT1b) and mitochondrial biogenesis (PGC-1α) in mice muscle. In ratmuscle, Compound I treatment increased the expression of a known PPARregulated target gene, Angiopoietin-like 4 (ANGPTL4).

The preparation and uses of Compound I have been previously described(see, WO 2007/071766, U.S. Pat. Nos. 7,943,613, 8,362,016, 8,551,993,9,663,481, 9,855,274, WO 2015/035171, U.S. Pat. Nos. 9,487,493,9,968,613, each of which is incorporated by reference in its entirety).

Compound I refers to(E)-2-(4-((3-(4-fluorophenyl)-3-(4-(3-morpholinoprop-1-yn-1-yl)phenyl)allyl)oxy)-2-methylphenoxy)aceticacid, which has the chemical structure shown below.

In some embodiments, Compound I exists in a zwitterionic form.

Compound II refers to sodium(E)-2-(44(3-(4-fluorophenyl)-3-(4-(3-morpholinoprop-1-yn-1-yl)phenyl)allyl)oxy)-2-methylphenoxy)acetate,which has the chemical structure shown below.

In some embodiments, Compound II is amorphous.

As used herein, the term “amorphous” or “amorphous solid form” refers toa solid form lacking crystallinity.

In some embodiments, Compound II is crystalline.

In some embodiments, crystallinity of a solid form is determined bymethods known in the art. In some embodiments, crystallinity of a solidform is determined by X-Ray Powder Diffraction (XRPD). In someembodiments, crystallinity of a solid form is determined by solid stateNMR.

Amorphous Compound II

Provided herein is the amorphous Compound II. Some embodiments provide acomposition comprising amorphous Compound II. In some embodiments,amorphous Compound II has one of the following properties:

-   -   a) an XRPD pattern showing a lack of crystallinity;    -   b) a DSC thermogram substantially the same as shown in FIG. 22 ;    -   c) a DSC thermogram with:        -   i. a broad endotherm with onset at 43.1° C. and peak at            about 60.3° C.;        -   ii. a broad exotherm with onset at 107.0° C. and peak at            112.9° C.; and        -   iii. an endotherm with onset at 125.0° C. peak a 130.4° C.;    -   d) a TGA pattern substantially the same as shown in FIG. 23 ;    -   e) a TGA pattern with a 3.7% w/w loss from 25 to 150° C., and a        degradation onset at about 260° C.;    -   f) an unchanged XRPD after storage at ambient temperature over        24 hours, 48 hours, 7 days, or days;    -   g) an unchanged XRPD after storage at 75% RH and 40° C. over 10        days; or    -   h) combinations thereof.

In some embodiments, amorphous Compound II has an XRPD pattern showing alack of crystallinity. In some embodiments, amorphous Compound II has anXRPD pattern substantially the same as shown in FIG. 21 . In someembodiments, amorphous Compound II has a DSC thermogram substantiallythe same as shown in FIG. 22 . In some embodiments, amorphous CompoundII has a DSC thermogram with: a broad endotherm with onset at 43.1° C.and peak at about 60.3° C.; a broad exotherm with onset at 107.0° C. andpeak at 112.9° C.; and an endotherm with onset at 125.0° C. peak a130.4° C. In some embodiments, amorphous Compound II has a TGA patternsubstantially the same as shown in FIG. 23 . In some embodiments,amorphous Compound II has a TGA pattern with a 3.7% w/w loss from 25 to150° C., and a degradation onset at about 260° C. In some embodiments,amorphous Compound II has an unchanged XRPD after storage at ambienttemperature over 24 hours, 48 hours, 7 days, or 10 days. In someembodiments, amorphous Compound II exhibits an unchanged XRPD after theGVS analysis at 75% RH and 40° C. over 10 days.

In some embodiments, amorphous Compound II is substantially free ofimpurities. In some embodiments, amorphous Compound II is at least about90% pure. In some embodiments, amorphous Compound II is at least about95%, about 96%, about 97%, about 98%, or about 99% pure. In someembodiments, amorphous Compound II is at least about 95% pure. In someembodiments, amorphous Compound II is at least about 96% pure. In someembodiments, amorphous Compound II is at least about 97% pure. In someembodiments, amorphous Compound II is at least about 98% pure. In someembodiments, amorphous Compound II is at least about 99% pure. In someembodiments, amorphous Compound II is at least about 99.1%, about 99.2%,about 99.3%, about 99.4%, about 99.5%, about 99.6%, about 99.7%, about99.8%, about 99.9%, or about 100% pure.

Crystalline Compound II

Also provided herein is crystalline Compound II.

In some embodiments, the crystalline Compound II is unsolvated.

In some embodiments, the crystalline Compound II is solvated. In someembodiments, the crystalline Compound II is an acetone solvate,1-propanol solvate, 2-methyltetrahydrofuran solvate, methyl isobutylketone solvate, 1,4-dioxane solvate, chloroform solvate, tetrahydrofuransolvate, or dichloromethane solvate. In some embodiments, thecrystalline Compound II is an acetone solvate. In some embodiments, thecrystalline Compound II is a 2-methyltetrahydrofuran solvate. In someembodiments, the crystalline Compound II is a tetrahydrofuran solvate.

In some embodiments, the crystalline Compound II is a hydrate.

In some embodiments, amorphous Compound II is substantially free ofimpurities. In some embodiments, amorphous Compound II is at least about90% pure. In some embodiments, amorphous Compound II is at least about95%, about 96%, about 97%, about 98%, or about 99% pure. In someembodiments, amorphous Compound II is at least about 95% pure. In someembodiments, amorphous Compound II is at least about 96% pure. In someembodiments, amorphous Compound II is at least about 97% pure. In someembodiments, amorphous Compound II is at least about 98% pure. In someembodiments, amorphous Compound II is at least about 99% pure. In someembodiments, amorphous Compound II is at least about 99.1%, about 99.2%,about 99.3%, about 99.4%, about 99.5%, about 99.6%, about 99.7%, about99.8%, about 99.9%, or about 100% pure.

Crystalline Form 1 of Compound II

In some embodiments, the crystalline Compound II is crystalline Form 1of Compound II. In some embodiments, described herein is a compositioncomprising crystalline Form 1 of Compound II. In some embodiments,crystalline Form 1 of Compound II is characterized as having:

-   -   a) an XRPD pattern substantially the same as shown in FIG. 1 ;    -   b) an XRPD pattern with peaks at about 2.8° 2-Theta, about 7.2°        2-Theta, about 13.4° 2-Theta, about 17.8° 2-Theta, about 19.7°        2-Theta, about 19.9° 2-Theta, and about 20.6° 2-Theta as        measured using Cu Kα radiation;    -   c) a DSC thermogram substantially the same as shown in FIG. 2 ;    -   d) a DSC thermogram with an endotherm having onset at about        179.5° C. and peak at about 181.6° C.;    -   e) a TGA pattern substantially the same as shown in FIG. 3 ;    -   f) a TGA pattern with a 0.1% w/w loss from 25 to 60° C. and        degradation onset at about 250° C.;    -   g) an FTIR spectroscopy pattern substantially the same as shown        in FIG. 4 ;    -   h) an FTIR spectroscopy pattern with peaks at about 103 cm⁻¹,        about 838 cm⁻¹, about 1220 cm⁻¹, about 1504 cm⁻¹, and about 1612        cm⁻¹;    -   i) a Raman spectroscopy pattern substantially the same as shown        in FIG. 5 ;    -   j) a Raman spectroscopy pattern with peaks at about 103 cm⁻¹,        about 126 cm⁻¹, about 810 cm⁻¹, about 1158 cm⁻¹, about 1238        cm⁻¹, about 1604 cm⁻¹, and about 1629 cm⁻¹;    -   k) unit cell parameters substantially equal to the following at        100 K:

Crystal System Monoclinic Space Group P2/c a (Å) 31.581(3) b (Å)6.1180(4) c (Å) 27.2046(18) α ° 90 β ° 94.447(7) γ ° 90 V (Å³) 5240.4(7)Z 8 Calculated Density (Mg/m³) 1.363 Absorption coefficient (mm⁻¹) 0.937F(000) 2256or

-   -   l) combinations thereof.

In some embodiments, crystalline Form 1 of Compound II has an XRPDpattern substantially the same as shown in FIG. 1 . In some embodiments,crystalline Form 1 of Compound II has an XRPD pattern with peaks atabout 2.8° 2-Theta, about 7.2° 2-Theta, about 13.4° 2-Theta, about 17.8°2-Theta, about 19.7° 2-Theta, about 19.9° 2-Theta, and about 20.6°2-Theta as measured using Cu Kα radiation. In some embodiments,crystalline Form 1 of Compound II has a DSC thermogram substantially thesame as shown in FIG. 2 . In some embodiments, crystalline Form 1 ofCompound II has a DSC thermogram with an endotherm having onset at about179.5° C. and peak at about 181.6° C. In some embodiments, crystallineForm 1 of Compound II has a TGA pattern substantially the same as shownin FIG. 3 . In some embodiments, crystalline Form 1 of Compound II has aTGA pattern with a 0.1% w/w loss from 25 to 60° C. and degradation onsetat about 250° C. In some embodiments, crystalline Form 1 of Compound IIhas an FTIR spectroscopy pattern substantially the same as shown in FIG.4 . In some embodiments, crystalline Form 1 of Compound II has an FTIRspectroscopy pattern with peaks at about 103 cm⁻¹, about 838 cm⁻¹, about1220 cm⁻¹, about 1504 cm⁻¹, and about 1612 cm⁻¹. In some embodiments,crystalline Form 1 of Compound II has a Raman spectroscopy patternsubstantially the same as shown in FIG. 5 . In some embodiments,crystalline Form 1 of Compound II has a Raman spectroscopy pattern withpeaks at about 103 cm⁻¹, about 126 cm⁻¹, about 810 cm⁻¹, about 1158cm⁻¹, about 1238 cm⁻¹, about 1604 cm⁻¹, and about 1629 cm⁻¹. In someembodiments, crystalline Form 1 of Compound II has a reversible wateruptake (˜13.0% w/w) between 0 and 90% Relative Humidity (RH).

In some embodiments, crystalline Form 1 of Compound II has unit cellparameters substantially equal to the following at 100 K:

Crystal System Monoclinic Space Group P2/c a (Å) 31.581(3) b (Å)6.1180(4) c (Å) 27.2046(18) α ° 90 β ° 94.447(7) γ ° 90 V (Å³) 5240.4(7)Z 8 Calculated Density (Mg/m³) 1.363 Absorption coefficient (mm⁻¹) 0.937F(000) 2256

In some embodiments, crystalline Form 1 of Compound II has an XRPDpattern reflection at about 2.8° 2-Theta as measured using Cu Kαradiation. In some embodiments, crystalline Form 1 is furthercharacterized by XRPD pattern reflections at about 7.2° 2-Theta, about13.4° 2-Theta, about 17.8° 2-Theta, about 19.7° 2-Theta, about 19.9°2-Theta, and about 20.6° 2-Theta. In some embodiments, crystalline Form1 is further characterized by at least one XRPD pattern reflectionselected from about 7.2° 2-Theta, about 13.4° 2-Theta, about 17.8°2-Theta, about 19.7° 2-Theta, about 19.9° 2-Theta, and about 20.6°2-Theta. In some embodiments, crystalline Form 1 is furthercharacterized by at least two XRPD pattern reflections selected fromabout 7.2° 2-Theta, about 13.4° 2-Theta, about 17.8° 2-Theta, about19.7° 2-Theta, about 19.9° 2-Theta, and about 20.6° 2-Theta. In someembodiments, crystalline Form 1 is further characterized by at leastthree XRPD pattern reflections selected from about 7.2° 2-Theta, about13.4° 2-Theta, about 17.8° 2-Theta, about 19.7° 2-Theta, about 19.9°2-Theta, and about 20.6° 2-Theta.

Crystalline Form 2 of Compound II

In some embodiments, crystalline Compound II is crystalline Form 2 ofCompound II. Crystalline Form 2 is a hydrate of Compound II. In someembodiments, described herein is a composition comprising crystallineForm 2 of Compound II. In some embodiments, crystalline Form 2 ofCompound II is characterized as having:

-   -   a) an XRPD pattern substantially the same as shown in FIG. 6 ;    -   b) an XRPD pattern with peaks at about 4.5 2-Theta, about 13.8°        2-Theta, about 17.6° 2-Theta, about 19.0° 2-Theta, about 19.6°        2-Theta, about 19.9° 2-Theta, about 20.5° 2-Theta, and about        23.0° 2-Theta as measured using Cu Kα radiation;    -   c) a DSC thermogram substantially the same as shown in FIG. 7 ;    -   d) a DSC thermogram with six endothermic events having:        -   i. an onset at about 44.1° C. and a peak at about 72.4° C.;        -   ii. a peak at about 92.4° C.;        -   iii. an onset at about 107.0° C. and a peak at about 118.5°            C.;        -   iv. an onset at about 127.6° C. and a peak at about 130.0°            C.;        -   v. an onset at about 146.9° C. and a peak at about 149.9°            C.; and        -   vi. an onset at about 179.5° C. and a peak at about 181.1°            C.;    -   e) a TGA pattern substantially the same as shown in FIG. 8 ;    -   f) a TGA pattern with a 17.2% w/w loss from 25 to 145° C., and        degradation onset at about 275° C.;    -   g) reversible water uptake (˜25% w/w) between 0 and 90% Relative        Humidity (RH);    -   h) an unchanged XRPD after GVS analysis at 90% RH and 25° C.;    -   i) an unchanged XRPD after storage at 97% RH and 25° C. over 7        days;    -   j) an unchanged XRPD after storage at 75% RH and 40° C. over 7        days; or    -   k) combinations thereof.

In some embodiments, crystalline Form 2 of Compound II has an XRPDpattern substantially the same as shown in FIG. 6 . In some embodiments,crystalline Form 2 of Compound II has an XRPD pattern with peaks atabout 4.5 2-Theta, about 13.8° 2-Theta, about 17.6° 2-Theta, about 19.0°2-Theta, about 19.6° 2-Theta, about 19.9° 2-Theta, about 20.5° 2-Theta,and about 23.0° 2-Theta as measured using Cu Kα radiation. In someembodiments, crystalline Form 2 of Compound II has a DSC thermogramsubstantially the same as shown in FIG. 7 . In some embodiments,crystalline Form 2 of Compound II has a DSC thermogram with sixendothermic events having: an onset at about 44.1° C. and a peak atabout 72.4° C.; a peak at about 92.4° C.; an onset at about 107.0° C.and a peak at about 118.5° C.; an onset at about 127.6° C. and a peak atabout 130.0° C.; an onset at about 146.9° C. and a peak at about 149.9°C.; and an onset at about 179.5° C. and a peak at about 181.1° C. Insome embodiments, Form 2 of Compound II has a TGA pattern substantiallythe same as shown in FIG. 8 . In some embodiments, crystalline Form 2 ofCompound II has a TGA pattern with a 17.2% w/w loss from 25 to 145° C.,and degradation onset at about 275° C. In some embodiments, crystallineForm 2 of Compound II has reversible water uptake (˜25% w/w) between 0and 90% Relative Humidity (RH). In some embodiments, crystalline Form 2of Compound II an unchanged XRPD after GVS analysis at 90% RH and 25° C.In some embodiments, crystalline Form 2 of Compound II has an unchangedXRPD after storage at 97% RH and 25° C. over 7 days. In someembodiments, crystalline Form 2 of Compound II has an unchanged XRPDafter storage at 75% RH and 40° C. over 7 days.

In some embodiments, crystalline Form 2 of Compound II has an XRPDpattern reflection at 4.5° 2-Theta as measured using Cu Kα radiation. Insome embodiments, crystalline Form 2 is further characterized by XRPDpattern reflections at about 13.8° 2-Theta, about 17.6° 2-Theta, about19.0° 2-Theta, about 19.6° 2-Theta, about 19.9° 2-Theta, about 20.5°2-Theta, and about 23.0° 2-Theta. In some embodiments, crystalline Form2 is further characterized by at least one XRPD pattern reflectionselected from about 13.8° 2-Theta, about 17.6° 2-Theta, about 19.0°2-Theta, about 19.6° 2-Theta, about 19.9° 2-Theta, about 20.5° 2-Theta,and about 23.0° 2-Theta. In some embodiments, crystalline Form 2 isfurther characterized by at least two XRPD pattern reflections selectedfrom about 13.8° 2-Theta, about 17.6° 2-Theta, about 19.0° 2-Theta,about 19.6° 2-Theta, about 19.9° 2-Theta, about 20.5° 2-Theta, and about23.0° 2-Theta. In some embodiments, crystalline Form 2 is furthercharacterized by at least three XRPD pattern reflections selected fromabout 13.8° 2-Theta, about 17.6° 2-Theta, about 19.0° 2-Theta, about19.6° 2-Theta, about 19.9° 2-Theta, about 20.5° 2-Theta, and about 23.0°2-Theta.

Crystalline Form 3 of Compound II

In some embodiments, crystalline Compound II is crystalline Form 3 ofCompound II. Crystalline Form 3 of Compound II is a solvate of CompoundII. In some embodiments, described herein is a composition comprisingcrystalline Form 3 of Compound II. In some embodiments, crystalline Form3 of Compound II is an isostructural solvate form that is formed withmultiple solvents. In some embodiments, crystalline Form 3 of CompoundII is a solvate with toluene, methyl isobutyl ketone (MIBK), or2-methyltetrahydrofuran.

In some embodiments, crystalline Form 3 of Compound II is a crystalline2-methyltetrahydrofuran solvate of Compound II.

In some embodiments, crystalline Form 3 of Compound II is characterizedas having:

-   -   a) an XRPD pattern substantially the same as shown in FIG. 9 ;    -   b) a DSC thermogram substantially the same as shown in FIG. 10 ;    -   c) a DSC thermogram with three endothermic events having:        -   i. an onset at about 58.7° C. and a peak at about 73.2° C.;        -   ii. an onset at about 114.5° C. and a peak at about 136.2°            C.; and        -   iii. an onset at about 172.5° C. and a peak at about 178.6°            C.;    -   d) a TGA pattern substantially the same as shown in FIG. 11 ;    -   e) a TGA pattern with a 2.3% w/w loss from 25 to 82° C., a        further 3.8% w/w loss from 82° C. to 155° C., and a degradation        onset at about 275° C.;    -   f) reversible water uptake (˜9.0% w/w) between 0 and 90%        Relative Humidity (RH);    -   g) an XRPD that converts to Form 1 after GVS analysis at 90% RH        and 25° C.;    -   h) an XRPD that converts to Form 1 after storage at 75% RH and        40° C. for 7 days; or    -   i) combinations thereof.

In some embodiments, crystalline Form 3 of Compound II has an XRPDpattern substantially the same as shown in FIG. 9 . In some embodiments,crystalline Form 3 of Compound II has a DSC thermogram substantially thesame as shown in FIG. 10 . In some embodiments, crystalline Form 3 ofCompound II has a DSC thermogram with three endothermic events having:an onset at about 58.7° C. and a peak at about 73.2° C.; an onset atabout 114.5° C. and a peak at about 136.2° C.; an onset at about 172.5°C. and a peak at about 178.6° C. In some embodiments, crystalline Form 3of Compound II has a TGA pattern substantially the same as shown in FIG.11 . In some embodiments, crystalline Form 3 of Compound II has a TGApattern with a 2.3% w/w loss from 25 to 82° C., a further 3.8% w/w lossfrom 82° C. to 155° C., and a degradation onset at about 275° C. In someembodiments, crystalline Form 3 of Compound II has reversible wateruptake (˜9.0% w/w) between 0 and 90% Relative Humidity (RH). In someembodiments, crystalline Form 3 of Compound II has an XRPD that convertsto Form 1 after GVS analysis at 90% RH and 25° C. In some embodiments,crystalline Form 3 of Compound II has an XRPD that converts to Form 1after storage at 75% RH and 40° C. for 7 days.

In some embodiments, the crystalline Form 3 of Compound II is unstableand converts to Form 1 on drying. In some embodiments, the crystallineForm 3 of Compound II is unstable and converts to Form 1 on standing inambient conditions.

Crystalline Form 4 of Compound II

In some embodiments, crystalline Compound II is crystalline Form 4 ofCompound II. Crystalline Form 4 of Compound II is a solvate. In someembodiments, described herein is a composition comprising crystallineForm 4 of Compound II. In some embodiments, crystalline Form 4 ofCompound II is an isostructural solvate form that is formed withmultiple solvents. In some embodiments, crystalline Form 4 of CompoundII is solvated with methyl isobutyl ketone, 1,4-dioxane, chloroform,tetrahydrofuran, or dichloromethane.

In some embodiments, crystalline Form 4 of Compound II is atetrahydrofuran solvate.

In some embodiments, crystalline Form 4 of Compound II is characterizedas having:

-   -   a) an XRPD pattern substantially the same as shown in FIG. 12 ;    -   b) an XRPD pattern with peaks at about 3.3° 2-Theta, about 6.7°        2-Theta, about 20.1° 2-Theta, and about 20.7° 2-Theta as        measured using Cu Kα radiation;    -   c) a DSC thermogram substantially the same as shown in FIG. 13 ;    -   d) a DSC thermogram with two endothermic events having:        -   i. an onset at about 111.7° C. and a peak at about 114.5° C.            with a broad shoulder starting at about 70° C.; and        -   ii. an onset at about 142.5° C. and a peak at about            147.2° C. with a broad shoulder starting at about 130.6° C.;    -   e) a TGA pattern substantially the same as shown in FIG. 14 ;    -   f) a TGA pattern with a 14.3% w/w loss from 25 to 175° C., and        degradation onset at about 285° C.;    -   g) reversible water uptake (˜23% w/w) between 0 and 90% Relative        Humidity (RH);    -   h) an XRPD that converts to Form 2 after GVS analysis at 90% RH        and 25° C.;    -   i) an unchanged XRPD after heating to 110° C.;    -   j) an XRPD that converts to Form 2 after storage at 97% RH and        25° C. over 7 days;    -   k) an XRPD that converts to Form 1 after storage at 75% RH and        40° C. over 7 days; or    -   1) combinations thereof.

In some embodiments, crystalline Form 4 of Compound II has an XRPDpattern substantially the same as shown in FIG. 12 . In someembodiments, crystalline Form 4 of Compound II has an XRPD pattern withpeaks at about 3.3° 2-Theta, about 6.7° 2-Theta, about 20.1° 2-Theta,and about 20.7° 2-Theta as measured using Cu Kα radiation. In someembodiments, crystalline Form 4 of Compound II has a DSC thermogramsubstantially the same as shown in FIG. 13 . In some embodiments,crystalline Form 4 of Compound II has a DSC thermogram with twoendothermic events having: an onset at about 111.7° C. and a peak atabout 114.5° C. with a broad shoulder starting at about 70° C.; and anonset at about 142.5° C. and a peak at about 147.2° C. with a broadshoulder starting at about 130.6° C. In some embodiments, crystallineForm 4 of Compound II has a TGA pattern substantially the same as shownin FIG. 14 . In some embodiments, crystalline Form 4 of Compound II hasa TGA pattern with a 14.3% w/w loss from 25 to 175° C., and degradationonset at about 285° C. In some embodiments, crystalline Form 4 ofCompound II has reversible water uptake (˜23% w/w) between 0 and 90%Relative Humidity (RH). In some embodiments, crystalline Form 4 ofCompound II has an XRPD that converts to Form 2 after GVS analysis at90% RH and 25° C. In some embodiments, crystalline Form 4 of Compound IIhas an unchanged XRPD after heating to 110° C. In some embodiments,crystalline Form 4 of Compound II has an XRPD that converts to Form 2after storage at 97% RH and 25° C. over 7 days. In some embodiments,crystalline Form 4 of Compound II has an XRPD that converts to Form 1after storage at 75% RH and 40° C. over 7 days.

In some embodiments, crystalline Form 4 of Compound II has an XRPDpattern reflection at 3.3° 2-Theta as measured using Cu Kα radiation. Insome embodiments, crystalline Form 4 is further characterized by XRPDpattern reflections at 20.1° 2-Theta and 20.7° 2-Theta. In someembodiments, crystalline Form 4 is further characterized by XRPD patternreflections at 5.7° 2-Theta, 11.9° 2-Theta, 17.2° 2-Theta, 17.4°2-Theta, 18.1° 2-Theta, 19.1° 2-Theta, 19.8° 2-Theta, 22.9° 2-Theta, and23.1° 2-Theta. In some embodiments, crystalline Form 4 is furthercharacterized by at least one XRPD pattern reflection selected from 5.7°2-Theta, 11.9° 2-Theta, 17.2° 2-Theta, 17.4° 2-Theta, 18.1° 2-Theta,19.1° 2-Theta, 19.8° 2-Theta, 22.9° 2-Theta, and 23.1° 2-Theta. In someembodiments, crystalline Form 4 is further characterized by at least twoXRPD pattern reflections selected from 5.7° 2-Theta, 11.9° 2-Theta,17.2° 2-Theta, 17.4° 2-Theta, 18.1° 2-Theta, 19.1° 2-Theta, 19.8°2-Theta, 22.9° 2-Theta, and 23.1° 2-Theta. In some embodiments,crystalline Form 4 is further characterized by at least three XRPDpattern reflections selected from 5.7° 2-Theta, 11.9° 2-Theta, 17.2°2-Theta, 17.4° 2-Theta, 18.1° 2-Theta, 19.1° 2-Theta, 19.8° 2-Theta,22.9° 2-Theta, and 23.1° 2-Theta.

Crystalline Form 5 of Compound II

In some embodiments, crystalline Compound II is crystalline Form 5 ofCompound II. Crystalline Form 5 of Compound II is a solvate. In someembodiments, described herein is a composition comprising crystallineForm 5 of Compound II. In some embodiments, crystalline Form 5 ofCompound II is an isostructural solvate form that is formed withmultiple solvents. In some embodiments, crystalline Form 5 of CompoundII is solvated with acetone, methyl ethyl ketone, diethyl ether, orethyl acetate.

In some embodiments, crystalline Form 5 of Compound II is an acetonesolvate.

In some embodiments, crystalline Form 5 of Compound II is characterizedas having:

-   -   a) an XRPD pattern substantially the same as shown in FIG. 15 ;    -   b) an XRPD pattern with peaks at about 2.8 2-Theta, about 8.3°        2-Theta, about 8.7° 2-Theta, about 13.1° 2-Theta, about 19.4°        2-Theta, about 20.2° 2-Theta, about 21.3° 2-Theta, and about        24.6° 2-Theta as measured using Cu Kα radiation;    -   c) a DSC thermogram substantially the same as shown in FIG. 16 ;    -   d) a DSC thermogram with two endothermic events having:        -   i. an onset at 75.8° C. and two peaks at about 85.8° C. and            97.2° C.; and        -   ii. onset at 180.4° C. and a peak at 182.2;    -   e) an FTIR spectroscopy pattern substantially the same as shown        in FIG. 17 ; or    -   f) an FTIR spectroscopy pattern with peaks at about 810 cm⁻¹,        about 838 cm⁻¹, about 1220 cm⁻¹, about 1504 cm⁻¹, and about 1612        cm⁻¹;        -   or    -   g) combinations thereof.

In some embodiments, crystalline Form 5 of Compound II has an XRPDpattern substantially the same as shown in FIG. 15 . In someembodiments, crystalline Form 5 of Compound II has an XRPD pattern withpeaks at about 2.8 2-Theta, about 8.3° 2-Theta, about 8.7° 2-Theta,about 13.1° 2-Theta, about 19.4° 2-Theta, about 20.2° 2-Theta, about21.3° 2-Theta, and about 24.6° 2-Theta as measured using Cu Kαradiation. In some embodiments, crystalline Form 5 of Compound II has aDSC thermogram substantially the same as shown in FIG. 16 . In someembodiments, crystalline Form 5 of Compound II has a DSC thermogram withtwo endothermic events having: an onset at 75.8° C. and two peaks atabout 85.8° C. and 97.2° C.; and onset at 180.4° C. and a peak at 182.2.In some embodiments, crystalline Form 5 of Compound II has an FTIRspectroscopy pattern substantially the same as shown in FIG. 17 . Insome embodiments, crystalline Form 5 of Compound II has an FTIRspectroscopy pattern with peaks at about 810 cm⁻¹, about 838 cm⁻¹, about1220 cm⁻¹, about 1504 cm⁻¹, and about 1612 cm⁻¹. In some embodiments,crystalline Form 5 of Compound II is unstable and converts to Form 1 ondrying. In some embodiments, crystalline Form 5 of Compound II has anXRPD that converts to Form 1 after drying. In some embodiments,crystalline Form 5 of Compound II has an XRPD that converts to Form 1after GVS analysis at 90% RH and 25° C.

In some embodiments, crystalline Form 5 of Compound II has an XRPDpattern reflection at 2.8° 2-Theta as measured using Cu Kα radiation. Insome embodiments, crystalline Form 5 is further characterized by XRPDpattern reflections at about 8.3° 2-Theta, about 8.7° 2-Theta, about13.1° 2-Theta, about 19.4° 2-Theta, about 20.2° 2-Theta, about 21.3°2-Theta, and about 24.6° 2-Theta. In some embodiments, crystalline Form5 is further characterized by at least one XRPD pattern reflectionselected from about 8.3° 2-Theta, about 8.7° 2-Theta, about 13.1°2-Theta, about 19.4° 2-Theta, about 20.2° 2-Theta, about 21.3° 2-Theta,and about 24.6° 2-Theta. In some embodiments, crystalline Form 5 isfurther characterized by at least two XRPD pattern reflections selectedfrom about 8.3° 2-Theta, about 8.7° 2-Theta, about 13.1° 2-Theta, about19.4° 2-Theta, about 20.2° 2-Theta, about 21.3° 2-Theta, and about 24.6°2-Theta. In some embodiments, crystalline Form 5 is furthercharacterized by at least three XRPD pattern reflections selected fromabout 8.3° 2-Theta, about 8.7° 2-Theta, about 13.1° 2-Theta, about 19.4°2-Theta, about 20.2° 2-Theta, about 21.3° 2-Theta, and about 24.6°2-Theta.

In some embodiments, disclosed herein is crystalline Compound IIsolvate. In some embodiments, the crystalline Compound II solvate is anisostructural solvate that is formed with multiple solvents. In someembodiments, the crystalline Compound II solvate is a solvate withdiethyl ether, ethyl acetate, methyl isobutyl ketone, methyl ethylketone, 1-propanol, 1,4-dioxane, toluene, chloroform, tetrahydrofuran,dichloromethane, or 2-methyltetrahydrofuran. In some embodiments, thecrystalline Compound II solvate is a crystalline solvate with1,4-dioxane, tetrahydrofuran, or 2-methyltetrahydrofuran.

In some embodiments, disclosed herein is a crystalline Compound IIhydrate.

Crystalline Pattern 9 of Compound II

In some embodiments, crystalline Compound II is crystalline Pattern 9 ofCompound II. Pattern 9 of Compound II is a hydrate. In some embodiments,crystalline Pattern 9 of Compound II is characterized as having:

-   -   a) an XRPD pattern substantially the same as shown in FIG. 18 ;    -   b) a DSC thermogram substantially the same as shown in FIG. 19 ;    -   c) a DSC thermogram with three endothermic events having:        -   i. an onset at about 38.5° C. and two peaks at about            71.5° C. and 94.1° C.;        -   ii. an onset at about 107.1° C. and two peaks at about            118.0° C. and 130.0° C.; and        -   iii. an onset at about 146.8° C. and a peak at about 150.0°            C.;    -   d) a TGA pattern substantially the same as shown in FIG. 20 ;    -   e) a TGA pattern with a 8.6% w/w loss from 25 to 105° C., and        degradation onset at about 270° C.;    -   f) reversible water uptake (˜27% w/w) between 0 and 90% Relative        Humidity (RH); and    -   g) an unchanged XRPD after GVS analysis at 90% RH and 25° C.; or    -   h) combinations thereof.

In some embodiments, crystalline Pattern 9 of Compound II has an XRPDpattern substantially the same as shown in FIG. 18 . In someembodiments, crystalline Pattern 9 of Compound II has a DSC thermogramsubstantially the same as shown in FIG. 19 . In some embodiments,crystalline Pattern 9 of Compound II has a DSC thermogram with threeendothermic events having: an onset at about 38.5° C. and two peaks atabout 71.5° C. and 94.1° C.; an onset at about 107.1° C. and two peaksat about 118.0° C. and 130.0° C.; and an onset at about 146.8° C. and apeak at about 150.0° C. In some embodiments, crystalline Pattern 9 ofCompound II has a TGA pattern substantially the same as shown in FIG. 20. In some embodiments, crystalline Pattern 9 of Compound II has a TGApattern with a 8.6% w/w loss from 25 to 105° C., and degradation onsetat about 270° C. In some embodiments, crystalline Pattern 9 of CompoundII has reversible water uptake (˜27% w/w) between 0 and 90% RelativeHumidity (RH). In some embodiments, crystalline Pattern 9 of Compound IIhas an unchanged XRPD after GVS analysis at 90% RH and 25° C.

In some embodiments, provided herein is crystalline Compound II2-methyltetrahydrofuran solvate (Pattern 5). In some embodiments, thecrystalline Compound II 2-methyltetrahydrofuran solvate (Pattern 5) isunstable.

In some embodiments, provided herein is crystalline Compound II1,4-dioxane solvate (Pattern 6). In some embodiments, the crystallineCompound II 1,4-dioxane solvate (Pattern 6) is unstable.

In some embodiments, provided herein is crystalline Compound II solvatePattern 8. In some embodiments, crystalline Compound II solvate Pattern8 is an isostructural solvate form that is formed with multiplesolvents. In some embodiments, crystalline Compound II solvate Pattern 8is a crystalline solvate with ethyl acetate. In some embodiments, thecrystalline Compound II solvate Pattern 8 is unstable and converts toForm 1 on drying.

In some embodiments, provided herein is crystalline Compound II solvatePattern 12. In some embodiments, crystalline Compound II Pattern 12 ischaracterized as having:

-   -   a) an XRPD pattern substantially the same as shown in FIG. 24 ;    -   b) a DSC thermogram substantially the same as shown in FIG. 25 ;    -   c) a DSC thermogram with five endothermic events having:        -   i. an onset at about 54.7° C. and peak at about 81.5° C.;        -   ii. an onset at about 90.1° C. and peak at about 92.2° C.;        -   iii. an onset at about 115.9° C. and peak at about 124.6°            C.;        -   iv. an onset at about 131.3° C. and peak at about 132.5° C.;            and        -   v. an onset at about 146.8° C. and peak at about 150.6° C.;            or    -   d) combinations thereof.

In one aspect, described herein is a process for the preparation ofsodium(E)-2-(4-((3-(4-fluorophenyl)-3-(4-(3-morpholinoprop-1-yn-1-yl)phenyl)allyl)oxy)-2-methylphenoxy)acetate(Compound II):

-   -   comprising treating:    -   Compound I:

-   -   or the alkyl ester of Compound I, or a salt thereof:

-   -   wherein R is C₁-C₆ alkyl;    -   with a sodium hydroxide solution in the presence of a suitable        solvent to provide Compound II.

In some embodiments, R is methyl, ethyl, propyl, isopropyl, butyl,isobutyl, tert-butyl, isoamyl, pentyl, or hexyl. In some embodiments, Ris methyl or ethyl. In some embodiments, R is methyl. In someembodiments, R is ethyl.

In some embodiments, the suitable solvent is water, methanol, ethanol,tetrahydrofuran, ethyl acetate, acetone, acetonitrile, or a combinationthereof.

In some embodiments, the preparation of the Compound II comprisestreating Compound I with a sodium hydroxide solution in the presence ofa suitable solvent, wherein the suitable solvent is water, methanol,ethanol, tetrahydrofuran, ethyl acetate, acetone, acetonitrile, or acombination thereof.

In some embodiments, the preparation of the Compound II comprisestreating Compound I with a sodium hydroxide solution in the presence ofa suitable solvent, wherein the suitable solvent is a combination ofacetone and acetonitrile. In some embodiments, Compound II isCrystalline Form 1 as described herein.

“Pharmaceutically acceptable,” as used herein, refers a material, suchas a carrier or diluent, which does not abrogate the biological activityor properties of the compound, and is relatively nontoxic, i.e., thematerial is administered to an individual without causing undesirablebiological effects or interacting in a deleterious manner with any ofthe components of the composition in which it is contained.

The term “pharmaceutically acceptable salt” refers to a form of atherapeutically active agent that consists of a cationic form of thetherapeutically active agent in combination with a suitable anion, or inalternative embodiments, an anionic form of the therapeutically activeagent in combination with a suitable cation. Handbook of PharmaceuticalSalts: Properties, Selection and Use. International Union of Pure andApplied Chemistry, Wiley-VCH 2002. S. M. Berge, L. D. Bighley, D.C.Monkhouse, J. Pharm. Sci. 1977, 66, 1-19. P. H. Stahl and C. G. Wermuth,editors, Handbook of Pharmaceutical Salts: Properties, Selection andUse, Weinheim/Zürich:Wiley-VCH/VHCA, 2002. Pharmaceutical saltstypically are more soluble and more rapidly soluble in stomach andintestinal juices than non-ionic species and so are useful in soliddosage forms. Furthermore, because their solubility often is a functionof pH, selective dissolution in one or another part of the digestivetract is possible and this capability can be manipulated as one aspectof delayed and sustained release behaviors. Also, because thesalt-forming molecule can be in equilibrium with a neutral form, passagethrough biological membranes can be adjusted.

In some embodiments, pharmaceutically acceptable salts are obtained byreacting a compound disclosed herein with an acid. In some embodiments,the compound disclosed herein (i.e. free base form) is basic and isreacted with an organic acid or an inorganic acid. Inorganic acidsinclude, but are not limited to, hydrochloric acid, hydrobromic acid,sulfuric acid, phosphoric acid, nitric acid, and metaphosphoric acid.Organic acids include, but are not limited to, 1-hydroxy-2-naphthoicacid; 2,2-dichloroacetic acid; 2-hydroxyethanesulfonic acid;2-oxoglutaric acid; 4-acetamidobenzoic acid; 4-aminosalicylic acid;acetic acid; adipic acid; ascorbic acid (L); aspartic acid (L);benzenesulfonic acid; benzoic acid; camphoric acid (+);camphor-10-sulfonic acid (+); capric acid (decanoic acid); caproic acid(hexanoic acid); caprylic acid (octanoic acid); carbonic acid; cinnamicacid; citric acid; cyclamic acid; dodecylsulfuric acid;ethane-1,2-disulfonic acid; ethanesulfonic acid; formic acid; fumaricacid; galactaric acid; gentisic acid; glucoheptonic acid (D); gluconicacid (D); glucuronic acid (D); glutamic acid; glutaric acid;glycerophosphoric acid; glycolic acid; hippuric acid; isobutyric acid;lactic acid (DL); lactobionic acid; lauric acid; maleic acid; malic acid(−L); malonic acid; mandelic acid (DL); methanesulfonic acid;naphthalene-1,5-disulfonic acid; naphthalene-2-sulfonic acid; nicotinicacid; oleic acid; oxalic acid; palmitic acid; pamoic acid; phosphoricacid; proprionic acid; pyroglutamic acid (−L); salicylic acid; sebacicacid; stearic acid; succinic acid; sulfuric acid; tartaric acid (+L);thiocyanic acid; toluenesulfonic acid (p); and undecylenic acid.

In some embodiments, a compound disclosed herein is prepared as ahydrochloride salt.

In some embodiments, pharmaceutically acceptable salts are obtained byreacting a compound disclosed herein with a base. In some embodiments,the compound disclosed herein is acidic and is reacted with a base. Insuch situations, an acidic proton of the compound disclosed herein isreplaced by a metal ion, e.g., lithium, sodium, potassium, magnesium,calcium, or an aluminum ion. In some cases, compounds described hereincoordinate with an organic base, such as, but not limited to,ethanolamine, diethanolamine, triethanolamine, tromethamine, meglumine,N-methylglucamine, dicyclohexylamine, tris(hydroxymethyl)methylamine. Inother cases, compounds described herein form salts with amino acids suchas, but not limited to, arginine, lysine, and the like. Acceptableinorganic bases used to form salts with compounds that include an acidicproton, include, but are not limited to, aluminum hydroxide, calciumhydroxide, potassium hydroxide, sodium carbonate, potassium carbonate,sodium hydroxide, lithium hydroxide, and the like. In some embodiments,the compounds provided herein are prepared as a sodium salt, calciumsalt, potassium salt, magnesium salt, meglumine salt, N-methylglucaminesalt or ammonium salt.

In some embodiments, a compound disclosed herein is prepared as thesodium salt.

It should be understood that a reference to a pharmaceuticallyacceptable salt includes the solvent addition forms. In someembodiments, solvates contain either stoichiometric ornon-stoichiometric amounts of a solvent, and are formed during theprocess of crystallization with pharmaceutically acceptable solventssuch as water, ethanol, and the like. Hydrates are formed when thesolvent is water, or alcoholates are formed when the solvent is alcohol.Solvates of compounds described herein are conveniently prepared orformed during the processes described herein. In addition, the compoundsprovided herein optionally exist in unsolvated as well as solvatedforms.

In additional or further embodiments, the compounds described herein aremetabolized upon administration to an organism in need to produce ametabolite that is then used to produce a desired effect, including adesired therapeutic effect.

A “metabolite” of a compound disclosed herein is a derivative of thatcompound that is formed when the compound is metabolized. The term“active metabolite” refers to a biologically active derivative of acompound that is formed when the compound is metabolized. The term“metabolized,” as used herein, refers to the sum of the processes(including, but not limited to, hydrolysis reactions and reactionscatalyzed by enzymes) by which a particular substance is changed by anorganism. Thus, enzymes may produce specific structural alterations to acompound. For example, cytochrome P450 catalyzes a variety of oxidativeand reductive reactions while uridine diphosphate glucuronyltransferasescatalyze the transfer of an activated glucuronic-acid molecule toaromatic alcohols, aliphatic alcohols, carboxylic acids, amines and freesulfhydryl groups. Metabolites of the compounds disclosed herein areoptionally identified either by administration of compounds to a hostand analysis of tissue samples from the host, or by incubation ofcompounds with hepatic cells in vitro and analysis of the resultingcompounds.

Unless otherwise stated, the following terms used in this applicationhave the definitions given below. The use of the term “including” aswell as other forms, such as “include”, “includes,” and “included,” isnot limiting. The section headings used herein are for organizationalpurposes only and are not to be construed as limiting the subject matterdescribed.

As used herein, “alkyl” refers to an aliphatic hydrocarbon group. Thealkyl group is branched or straight chain. In some embodiments, the“alkyl” group has 1 to 10 carbon atoms, i.e. a C₁-C₁₀alkyl. In someembodiments, an alkyl is a C₁-C₆alkyl. In one aspect the alkyl ismethyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, ort-butyl. Typical alkyl groups include, but are in no way limited to,methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, isoamyl,pentyl, and hexyl.

The term “acceptable” with respect to a formulation, composition oringredient, as used herein, means having no persistent detrimentaleffect on the general health of the subject being treated.

The term “modulate” as used herein, means to interact with a targeteither directly or indirectly so as to alter the activity of the target,including, by way of example only, to enhance the activity of thetarget, to inhibit the activity of the target, to limit the activity ofthe target, or to extend the activity of the target.

The term “modulator” as used herein, refers to a molecule that interactswith a target either directly or indirectly. The interactions include,but are not limited to, the interactions of an agonist, partial agonist,an inverse agonist, antagonist, degrader, or combinations thereof. Insome embodiments, a modulator is an agonist.

The terms “administer,” “administering”, “administration,” and the like,as used herein, refer to the methods that may be used to enable deliveryof compounds or compositions to the desired site of biological action.These methods include, but are not limited to oral routes, intraduodenalroutes, parenteral injection (including intravenous, subcutaneous,intraperitoneal, intramuscular, intravascular or infusion), topical andrectal administration. Those of skill in the art are familiar withadministration techniques that can be employed with the compounds andmethods described herein. In some embodiments, the compounds andcompositions described herein are administered orally.

The terms “co-administration” or the like, as used herein, are meant toencompass administration of the selected therapeutic agents to a singlepatient, and are intended to include treatment regimens in which theagents are administered by the same or different route of administrationor at the same or different time.

The terms “effective amount” or “therapeutically effective amount,” asused herein, refer to a sufficient amount of an agent or a compoundbeing administered, which will relieve to some extent one or more of thesymptoms of the disease or condition being treated. The result includesreduction and/or alleviation of the signs, symptoms, or causes of adisease, or any other desired alteration of a biological system. Forexample, an “effective amount” for therapeutic uses is the amount of thecomposition comprising a compound as disclosed herein required toprovide a clinically significant decrease in disease symptoms. Anappropriate “effective” amount in any individual case is optionallydetermined using techniques, such as a dose escalation study.

The terms “enhance” or “enhancing,” as used herein, means to increase orprolong either in potency or duration a desired effect. Thus, in regardto enhancing the effect of therapeutic agents, the term “enhancing”refers to the ability to increase or prolong, either in potency orduration, the effect of other therapeutic agents on a system. An“enhancing-effective amount,” as used herein, refers to an amountadequate to enhance the effect of another therapeutic agent in a desiredsystem.

The term “pharmaceutical combination” as used herein, means a productthat results from the mixing or combining of more than one activeingredient and includes both fixed and non-fixed combinations of theactive ingredients. The term “fixed combination” means that the activeingredients, e.g. a compound disclosed herein, or a pharmaceuticallyacceptable salt thereof, and a co-agent, are both administered to apatient simultaneously in the form of a single entity or dosage. Theterm “non-fixed combination” means that the active ingredients, e.g. acompound disclosed herein, or a pharmaceutically acceptable saltthereof, and a co-agent, are administered to a patient as separateentities either simultaneously, concurrently or sequentially with nospecific intervening time limits, wherein such administration provideseffective levels of the two compounds in the body of the patient. Thelatter also applies to cocktail therapy, e.g. the administration ofthree or more active ingredients.

The terms “article of manufacture” and “kit” are used as synonyms.

The term “subject” or “patient” encompasses mammals. Examples of mammalsinclude, but are not limited to, any member of the Mammalian class:humans, non-human primates such as chimpanzees, and other apes andmonkey species; farm animals such as cattle, horses, sheep, goats,swine; domestic animals such as rabbits, dogs, and cats; laboratoryanimals including rodents, such as rats, mice and guinea pigs, and thelike. In one aspect, the mammal is a human.

The terms “treat,” “treating” or “treatment,” as used herein, includealleviating, abating or ameliorating at least one symptom of a diseaseor condition, preventing additional symptoms, inhibiting the disease orcondition, e.g., arresting the development of the disease or condition,relieving the disease or condition, causing regression of the disease orcondition, relieving a condition caused by the disease or condition, orstopping the symptoms of the disease or condition eitherprophylactically and/or therapeutically.

Pharmaceutical Compositions

In some embodiments, the compounds and solid state forms describedherein are formulated into pharmaceutical compositions. Pharmaceuticalcompositions are formulated in a conventional manner using one or morepharmaceutically acceptable inactive ingredients that facilitateprocessing of the active compounds into preparations that are usedpharmaceutically. Proper formulation is dependent upon the route ofadministration chosen. A summary of pharmaceutical compositionsdescribed herein is found, for example, in Remington: The Science andPractice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack PublishingCompany, 1995); Hoover, John E., Remington's Pharmaceutical Sciences,Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H. A. andLachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York,N.Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems,Seventh Ed. (Lippincott Williams & Wilkins 1999), herein incorporated byreference for such disclosure.

In some embodiments, the compounds and solid state forms describedherein are administered either alone or in combination withpharmaceutically acceptable carriers, excipients or diluents, in apharmaceutical composition. Administration of the compounds andcompositions described herein can be effected by any method that enablesdelivery of the compounds to the site of action.

In some embodiments, pharmaceutical compositions suitable for oraladministration are presented as discrete units such as capsules, cachetsor tablets each containing a predetermined amount of the activeingredient; as a powder or granules; as a solution or a suspension in anaqueous liquid or a non-aqueous liquid; or as an oil-in-water liquidemulsion or a water-in-oil liquid emulsion. In some embodiments, theactive ingredient is presented as a bolus, electuary or paste.

Pharmaceutical compositions which can be used orally include tablets,push-fit capsules made of gelatin, as well as soft, sealed capsules madeof gelatin and a plasticizer, such as glycerol or sorbitol. Tablets maybe made by compression or molding, optionally with one or more accessoryingredients. Compressed tablets may be prepared by compressing in asuitable machine the active ingredient in a free-flowing form such as apowder or granules, optionally mixed with binders, inert diluents, orlubricating, surface active or dispersing agents. Molded tablets may bemade by molding in a suitable machine a mixture of the powdered compoundmoistened with an inert liquid diluent. In some embodiments, the tabletsare coated or scored and are formulated so as to provide slow orcontrolled release of the active ingredient therein. All formulationsfor oral administration should be in dosages suitable for suchadministration. The push-fit capsules can contain the active ingredientsin admixture with filler such as lactose, binders such as starches,and/or lubricants such as talc or magnesium stearate and, optionally,stabilizers. In soft capsules, the active compounds may be dissolved orsuspended in suitable liquids, such as fatty oils, liquid paraffin, orliquid polyethylene glycols. In some embodiments, stabilizers are added.Dragee cores are provided with suitable coatings. For this purpose,concentrated sugar solutions may be used, which may optionally containgum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethyleneglycol, and/or titanium dioxide, lacquer solutions, and suitable organicsolvents or solvent mixtures. Dyestuffs or pigments may be added to thetablets or Dragee coatings for identification or to characterizedifferent combinations of active compound doses.

It should be understood that in addition to the ingredients particularlymentioned above, the compounds and compositions described herein mayinclude other agents conventional in the art having regard to the typeof formulation in question, for example those suitable for oraladministration may include flavoring agents.

Methods of Dosing and Treatment Regimens

In one embodiment, the compounds and solid state forms disclosed herein,or a pharmaceutically acceptable salt thereof, are used in thepreparation of medicaments for the treatment of diseases or conditionsin a mammal that would benefit from modulation of PPARδ activity.Methods for treating any of the diseases or conditions described hereinin a mammal in need of such treatment, involves administration ofpharmaceutical compositions that include at least one compound disclosedherein or a pharmaceutically acceptable salt, active metabolite,prodrug, or pharmaceutically acceptable solvate thereof, intherapeutically effective amounts to said mammal.

In certain embodiments, the compositions containing the compounds andsolid state forms described herein are administered for prophylacticand/or therapeutic treatments. In certain therapeutic applications, thecompositions are administered to a patient already suffering from adisease or condition, in an amount sufficient to cure or at leastpartially arrest at least one of the symptoms of the disease orcondition. Amounts effective for this use depend on the severity andcourse of the disease or condition, previous therapy, the patient'shealth status, weight, and response to the drugs, and the judgment ofthe treating physician. Therapeutically effective amounts are optionallydetermined by methods including, but not limited to, a dose escalationand/or dose ranging clinical trial.

The amount of a given agent that corresponds to such an amount variesdepending upon factors such as the particular compound, diseasecondition and its severity, the identity (e.g., weight, sex) of thesubject or host in need of treatment, but nevertheless is determinedaccording to the particular circumstances surrounding the case,including, e.g., the specific agent being administered, the route ofadministration, the condition being treated, and the subject or hostbeing treated.

In general, however, doses employed for adult human treatment aretypically in the range of 0.01 mg-2000 mg per day. In one embodiment,the desired dose is conveniently presented in a single dose or individed doses administered simultaneously or at appropriate intervals,for example as two, three, four or more sub-doses per day.

In one embodiment, the daily dosages appropriate for the compound andsolid state forms disclosed herein, or a pharmaceutically acceptablesalt thereof, described herein are from about 0.01 to about 50 mg/kg perbody weight. In some embodiments, the daily dosage or the amount ofactive in the dosage form are lower or higher than the ranges indicatedherein, based on a number of variables in regard to an individualtreatment regime. In various embodiments, the daily and unit dosages arealtered depending on a number of variables including, but not limitedto, the activity of the compound used, the disease or condition to betreated, the mode of administration, the requirements of the individualsubject, the severity of the disease or condition being treated, and thejudgment of the practitioner.

In any of the aforementioned aspects are further embodiments in whichthe effective amount of the compound disclosed herein, or apharmaceutically acceptable salt thereof, is: (a) systemicallyadministered to the mammal; and/or (b) administered orally to themammal.

In some embodiments, compound II, a solid state form thereof, or apharmaceutically acceptable salt thereof, is administered is doseselected from about 25 mg, about 50 mg, about 75 mg, about 100 mg, about125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about375 mg, and about 400 mg. In some embodiments, the dose is administeredonce a day. In some embodiments, the dose is administered twice a day.

Articles of Manufacture and Kits

Disclosed herein, in certain embodiments, are kits and articles ofmanufacture for use with one or more methods described herein. In someembodiments, additional components of the kit comprises a carrier,package, or container that is compartmentalized to receive one or morecontainers such as vials, tubes, and the like, each of the container(s)comprising one of the separate elements to be used in a method describedherein. Suitable containers include, for example, bottles, vials,plates, syringes, and test tubes. In one embodiment, the containers areformed from a variety of materials such as glass or plastic.

The articles of manufacture provided herein contain packaging materials.Examples of pharmaceutical packaging materials include, but are notlimited to, bottles, tubes, bags, containers, and any packaging materialsuitable for a selected formulation and intended mode of use.

For example, the container(s) include one or more of the compoundsdescribed herein. Such kits optionally include an identifyingdescription or label or instructions relating to its use in the methodsdescribed herein.

A kit typically includes labels listing contents and/or instructions foruse, and package inserts with instructions for use. A set ofinstructions will also typically be included.

In one embodiment, a label is on or associated with the container. Inone embodiment, a label is on a container when letters, numbers or othercharacters forming the label are attached, molded or etched into thecontainer itself; a label is associated with a container when it ispresent within a receptacle or carrier that also holds the container,e.g., as a package insert. In one embodiment, a label is used toindicate that the contents are to be used for a specific therapeuticapplication. The label also indicates directions for use of thecontents, such as in the methods described herein.

EXAMPLES Abbreviations

-   -   2-Me-THF or 2-MeTHF=2-methyltetrahydrofuran;    -   ACID or MeCN=acetonitrile;    -   Compound        I=(E)-2-(4-((3-(4-fluorophenyl)-3-(4-(3-morpholinoprop-1-yn-1-yl)phenyl)allyl)oxy)-2-methylphenoxy)acetic        acid    -   Compound II=sodium        (E)-2-(4-((3-(4-fluorophenyl)-3-(4-(3-morpholinoprop-1-yn-1-yl)phenyl)allyl)oxy)-2-methylphenoxy)acetate    -   CPME=cyclopropyl methyl ether;    -   DCM=dichloromethane;    -   DI=deionized;    -   DSC=differential scanning calorimetry;    -   EtOAc=ethyl acetate;    -   EtOH=ethanol;    -   equiv or eq.=equivalent(s);    -   FTIR or FT-IR=Fourier transform infrared;    -   g=gram(s);    -   GC-MS or GCMS or GC/MS=gas chromatography-mass spectrometry;    -   GVS=gravimetric vapor sorption;    -   h or hr=hour;    -   hrs=hours;    -   HPLC=high-performance liquid chromatography;    -   IC=ion chromatography;    -   IPA=isopropyl alcohol;    -   IPAc=isopropyl acetate;    -   KF=Karl Fisher titration;    -   kg or KG or Kg=kilogram(s);    -   L=liter;    -   LAG=liquid assisted grinding;    -   LC-MS or LCMS or LC/MS=liquid chromatography-mass spectrometry;    -   M=molar;    -   MEK=methyl ethyl ketone;    -   MIBK=methyl isobutyl ketone;    -   MeOAc=methyl acetate;    -   MeOH=methanol;    -   mg=milligram(s);    -   mins or min=minutes;    -   mol.=mole;    -   mL or ml=milliliter;    -   μL=microliter;    -   MTBE or TBME=tert-butyl methyl ether;    -   NMP=N-methyl-2-pyrrolidone;    -   PPAR-delta or PPARδ=peroxisome proliferator-activated receptor        delta;    -   ppm=parts per million;    -   rbf or RBF=round bottom flask;    -   RH=relative humidity;    -   Rpm=revolutions per minute;    -   rt or RT=room temperature;    -   Rt=retention time;    -   TFA=trifluoroacetic acid;    -   TGA=thermogravimetric analysis;    -   THF=tetrahydrofuran;    -   vol or vols=volume(s);    -   w/w=weight ratio; and    -   XRPD=X-ray powder diffraction.

The following examples are provided for illustrative purposes only andnot to limit the scope of the claims provided herein.

Example 1: Preparation of(E)-2-(4((3-(4-fluorophenyl)-3-(4-(3-morpholinoprop-1-yn-1-yl)phenyl)ally)oxy)-2-methylphenoxy)aceticacid (Compound I)

The preparation of Compound I has been previously described (see, WO2007/071766, U.S. Pat. Nos. 7,943,613, 8,362,016, 8,551,993, 9,663,481,9,855,274, WO 2015/035171, U.S. Pat. Nos. 9,487,493, 9,968,613, each ofwhich is incorporated by reference in its entirety).

Example 2: Preparation of sodium(E)-2-(4-((3-(4-fluorophenyl)-3-(4-(3-morpholinoprop-1-yn-1-yl)phenyl)allyl)oxy)-2-methylphenoxy)acetate(Compound II)

To a 72 L open head round bottom flask containing a solution of compoundI (1089.4 g, 2.113 mol) in ethyl acetate (43 L) was added a solution ofsodium hydroxide (82.0 g, 2.050 mol) in water (675 ml). The solution washeated to 40° C. and was filtered. The filtrates were concentrated underreduced pressure at 40° C. until 35 L of solvent were removed. Thesolution was stirred at 20° C. for 1 hr and was filtered. The filtercake was washed with ethyl acetate (4 L) and air-dried on the filter for24 hrs followed by drying in a vacuum oven at 50° C. for 36 hrs toafford 1079.6 g of a beige solid. This solid was suspended in ethanol(22 L) in a 72 L rbf. The solution was stirred 3 hrs at room temp andthen was filtered. The filter cake was air-dried 2 hrs and then wasslurried with ethanol (2×4 L) followed by filtration. The filter cakewas air-dried 24 hrs and then transferred to a vacuum oven at 50° C. for24 hrs to afford Compound II (937.2 g. 82.5%) as a beige solid. Thisreaction was run twice in this manner to yield: 905.7 g (Sample #1,HPLC=99.85%, KF=0.65%, Acetic acid=19 ppm) and 968.7 g (Sample #2,HPLC=99.87%, KF=0.53%, Acetic acid=44 ppm). Total=1874.4 g (82.5%yield).

The two samples above were blended in a rotovap flask at roomtemperature for 1 hr to yield 1859.0 g of Compound II. The XRPD analysisof the collected solid was consistent with Compound II, Form 1. ¹H-NMRwas consistent with the structure.

Example 2-1: Preparation of Form 1 of Compound II

A solution of NaOH (1.1 eq) in water (1 ml/g) was added to Compound I inacetone (9 ml/g) at 50° C. and the mixture was stirred for 1-3 h toobtain a solution which was polish filtered. This solution was added toacetonitrile (12.5 ml/g), which was seeded with 4.2% w/w of Compound II(Form 1), at 35° C. over no less than 1.5 h. The resulting slurry wasstirred at 35° C. for 1-3 h, cooled to 5° C., filtered under N₂, andtwice washed with 2 ml/g cold acetone under a stream of N₂. The productwas then dried at 45-55° C. for 15-20 h. ¹H-NMR (300 MHz, 1:1CDCl₃/DMSO-d6): δ 7.45 (d, 2H), 7.22 (m, 2H), 7.15 (d, 2H), 7.04 (m,2H), 6.65 (d, 1H), 6.59 (d, 1H), 6.50 (dd, 1H), 6.24 (t, 1H), 4.44 (d,2H), 4.18 (s, 2H), 3.67 (m, 4H), 3.50 (s, 2H), 2.57 (m, 4H), 2.16 (s,3H). The XRPD analysis of the collected solid was consistent withCompound II, Form 1.

Example 3: Preparation of Amorphous Compound II from Crystalline Form 1of Compound II

Crystalline Form 1 of Compound II (500 mg) was dissolved in tBuOH/H₂O(1:1; 5.0 mL, vol) at RT and filtered through a 0.45 μm syringe tipfilter and transferred to a clean 100 ml RBF. The solution was frozen ina cardice-acetone bath and dried under vacuum overnight. The resultingsolid was analyzed by XRPD, ¹H-NMR, DSC, TGA, KF and HPLC. Data wasconsistent with the amorphous material.

One sample was retained for analysis whilst additional samples were usedas input to further polymorph screening.

Example 4: Preparation of Crystalline Hydrate Form 2 of Compound II fromCrystalline Form 1 of Compound II

Crystalline Form 1 of Compound II (4 g) was placed in a crystallizationdish and stored in a stability chamber at 25° C./97% RH. XRPD analysiswas regularly performed to verify the conversion to Form 2. Completeconversion was observed after 4 weeks at 25° C./97% RH.

The XRPD pattern was consistent with Form 2. The ¹H-NMR spectrum wasconsistent with the proposed structure.

Example 5: Preparation of Crystalline Acetone Solvate Form 5 of CompoundII from Crystalline Form 1 of Compound II

Crystalline Form 1 of Compound II (25 mg) was weighed into HPLC vialsand solvent was added (500 μl). The suspensions were stirred for 1 hr at35° C. before being analyzed by XRPD. For XRPD analysis, two drops ofsuspension were pipetted onto the sample holder using the 4-minutemethod.

Results of the solvent screen are found in the following table:

Solvent XRPD Acetone initially Form 5; reverts to Form 1 ACN Form 1Acetone:ACN (1:1) initially Form 5; reverts to Form 1 Acetone:Water(99:1) initially Form 5; reverts to Form 1 ACN:Water (99:1) Form 1Acetone:ACN:Water (49.5:49.5:1) initially Form 5; reverts to Form 1

The XRPD performed on the aliquots recovered from the solvent mixturesshowed that aliquots analyzed from acetone, acetone:acetonitrile,acetone:water and acetone:acetonitrile:water presented Form 5 initiallybut converted to Form 1 by the end of the run. The XRPD performed on thealiquots recovered from acetonitrile and acetonitrile:water showed thematerial remained as Form 1.

These additional experiments on Form 1 indicate that Form 5 is anacetone solvate as it was only observed from acetone and acetone solventmixtures. Slurries in acetonitrile showed that Form 1 remainedunchanged. Moreover, it was found that the conversion of Form 5 to Form1 is reversible under these conditions and that Form 5 is the moststable form in acetone solvent systems. Form 5 proved difficult toisolate and fully characterize.

Example 6: Preparation of Crystalline Tetrahydrofuran Solvate Form 4 ofCompound II from Crystalline Form 1 of Compound II

Crystalline Form 1 of Compound II (499.3 mg) was weighed into a 100 mlRBF with stir bar and THF (5 mL, 10 vol) was added at 60° C. The samplewas allowed to stir (500 rpm) for 24 h after which time an aliquot wastaken and analyzed by XRPD, showing Form 4 to have been produced. Thematerial was then isolated using a Buchner funnel and left to dry undersuction vacuum for about 45 mins. The sample was produced with a 70.8%yield, showed Form 4 by XRPD, and the ¹H-NMR spectrum was consistentwith the structure, showing 1.1 mol eq of THF.

Example 7: Preparation of Crystalline Pattern 9 of Compound II fromCrystalline Form 2 of Compound II

Crystalline Hydrate Form 2 of Compound II was portioned into two andhalf was placed in the vacuum oven at RT. After 24 h the sample wasanalyzed by XRPD. Some small differences between the XRPD pattern andthe Form 2 reference were noted. After 4 days in the vacuum ovencomplete conversion was observed. The material showed Pattern 9 by XRPDand a purity of 99.7%. The ¹H-NMR spectrum was consistent with theproposed structure and showed no residual solvent to be present.

Example 8: Polymorph Screen 1: Solvent Screen; Preparation of AdditionalSolid State Forms of Compound II

Crystalline Form 1 of Compound II (20 mg) was added into HPLC vials witha stir bar. Each sample was treated with increasing amounts of solvent(100-200 μL, 5-10 vol) at 25° C. After each addition the sample wasstirred for 20 min and observations recorded before further solventadditions. If complete dissolution was observed, no further additions ofsolvent were made. If dissolution was not observed in 100 vol solvent (2mL), the temperature was raised to 40° C. and held for 30 min toencourage dissolution. Clear solutions obtained were placed in thefridge (5° C.) and suspensions were matured (40° C./5° C., 8 h/cycle)for 24 h. After 24 hours an aliquot was taken (filtered and dried undersuction) and analyzed by XRPD.

Maturation and subsequent XRPD analysis of the suspensions showed eitherpoorly crystalline materials or XRPD patterns which matched or weresimilar to Form 1. A single sample, 2-methyltetrahydrofuran, showedsignificant enough differences to Form 1 for a new crystalline form tobe acknowledged. This was denoted as Form 3 and displayed an absence ofseveral Form 1 peaks at low 2θ values, as well as some peak shifts athigher 2θ angles.

All remaining material (suspensions or solutions) was placed forevaporation to encourage solid formation.

The evaporation of all the samples resulted in solids which displayedeither Form 1, either with or without some small additional peaks, orpredominantly amorphous samples by XRPD. Two samples, 1,4-dioxane andtetrahydrofuran, displayed a new pattern by XRPD, denoted as Form 4.

Example 9: Polymorph Screen 2: Low Temperature Slurry; Preparation ofAdditional Solid State Forms of Compound II

Amorphous Compound II was slurried in a selection of solvents (5, 10 or20 vol as appropriate to maintain adequate stirring) at 5° C. for 24 h.The slurries were then analyzed by XRPD.

After 24 h at 5° C. a number of samples showed differences by XRPD; fivesamples (methyl isobutyl ketone, 1,4-dioxane, chloroform,tetrahydrofuran, and dichloromethane) displayed Form 4, with varyinglevels of crystallinity and a single sample (diethyl ether) showed a newpattern, similar to a combination of Form 1 and Form 4 and was denotedas Form 5. A number of samples were poorly crystalline and a pattern notable to be identified, and the remainder of the samples displayed Form 1with varying degrees of crystallinity.

The slurries were left stirring at 5° C. and analyzed again after 4days.

After an extended period (4 days) at 5° C. the XPRD analysis resultswere similar, with a few samples displaying an increased level ofcrystallinity. Two samples showed a change relative to the 24 h data:2-methyltetrahydrofuran showed a more crystalline pattern than seenafter 24 h, which was denoted as Pattern 5, and EtOAc/H₂O (97.3:2.7)showed a poorly crystalline material with some differences with respectto the known patterns.

Example 10: Polymorph Screen 3: Liquid Assisted Grinding; Preparation ofAdditional Solid State Forms of Compound II

To the Amorphous Compound II, two small ball bearings were added alongwith the appropriate solvent (5 μL). The samples were subjected tomechanical stress using a Fritsch Planetary Mill (500 rpm, 2 h) andN-Methyl-2-Pyrrolidone the recovered materials analyzed by XRPD.

A number of samples (total of 10) remained amorphous or predominantlyamorphous with a single small peak between 2.8-3.0° 20, after thegrinding. Two samples, sample 14 (1,4-dioxane) and sample 16(chloroform) solvents respectively, displayed Form 4 by XRPD. A furtherfour samples also displayed differences by XRPD: samples 15 (toluene), 4(methyl isobutyl ketone), 19 (2-methyltetrahydrofuran) and 24(N-methyl-2-pyrrolidone). The latter three were identified as Form 3.The XRPD pattern obtained from sample 15 was denoted as Form 3. Theremainder of the samples converted to Form 1 during the grinding.

Example 11: Polymorph Screen 4: High Temperature Slurry; AdditionalSolid State Forms of Compound II

Appropriate solvent was added to Amorphous Compound II (300 μL, 10vol/150 μL, 5 vol) and slurried for 24 h at 60° C. Where necessary thesamples were left at either 50° C. or RT to slurry (solvent dependent).

The slurry samples were analyzed after 24 h and showed predominantlyForm 1 by XRPD, with varying degrees of crystallinity. Five samples,however, showed differences by XRPD: sample obtained from methylisobutyl ketone was assigned as Form 3, sample obtained from methylethyl ketone was assigned as Form 5, sample obtained from 1,4-dioxanewas assigned as pattern 6, sample obtained from tetrahydrofuran wasassigned as Form 4, and sample obtained from 2-methyltetrahydrofuran wasassigned as pattern 5 (poorly crystalline).

Example 12: Preparation of Crystalline Ethyl Acetate Solvate Pattern 8of Compound II from Amorphous Compound II

EtOAc/H₂O (97.3:2.7; 300 μL, 10 vol) was added to amorphous Compound IIand placed in the fridge under stirring. A portion was taken andanalyzed by XRPD after 24 h, and the slurry left stirring at 4° C. Thesample was further analyzed after 48 h and 6 days.

At all time-points analyzed, the same pattern was observed by XRPD,however this was different to that targeted in this experiment. The newpattern was denoted as Pattern 8.

Example 13: Preparation of Crystalline 2-methyltetrahydrofuran SolvateForm 3 of Compound II from Crystalline Form 1 of Compound II

Crystalline Form 1 of Compound II (506.8 mg) was weighed into a 100 mlRBF with stirrer bar and 2-methyltetrahydrofuran solvent (5 μL, 10 vol)added at 60° C. The sample was left to stir (500 rpm) for 3 days total,with an aliquot taken after 24 h and analyzed by XRPD. This showed thatPattern 5 had not been obtained and the sample was left for a prolongedduration.

After a further 2 days a second aliquot was taken and XPRD analysisindicated Form 3 to have formed. Additional 2-methyltetrahydrofuran (5μL, 10 vol) was added and the sample cooled to 5° C. and left to stirover the weekend. The sample was filtered using a Buchner funnel anddried under suction vacuum for 15 min.

The aliquots of the attempted scale up of Pattern 5 analyzed by XRPDdisplayed Form 3 during the preparation at high temperature. Uponcooling, the sample also displayed From 3. This XRPD pattern persistedupon isolation. The sample was prepared with a yield of 84%. The ¹H-NMRspectrum was consistent with the proposed structure and indicated 0.17mol eq residual 2-methyltetrahydrofuran to be present.

Example 14: Thermodynamic Stability and Preparation of CrystallinePattern 12 of Compound II

Competitive slurries aiming to determine the order of stability betweenForm 1 and Form 2 were performed in a range of water activities(0.4-0.8).

Crystalline Form 1 (2 g) and Crystalline Hydrate Form 2 (2 g) werelightly ground together using a mortar and pestle and then mixed using aroller mixer for approximately 2 hours. An XRPD was collected on thissample.

Saturated solutions at 5° C./25° C. were prepared by suspending themixed sample (200 mg) in 4 ml of the selected solvent and saturatedsolutions were prepared at 50° C. by suspending the mixed sample (100mg) in 1 ml of the selected solvent. The saturated solutions were leftstirring for 3 hrs at 25° C. and 50° C. The saturated solutions at 25°C. were filtered and split into solutions at ° C. and 25° C. The mixedsample (50 mg) was added to the filtered solutions. Two control samplesof Form 2 (50 mg) were prepared in 1 ml of acetone:water (99:1) andEtOH:water (95:5) and left stirring at 5° C., 25° C. and 50° C.

The samples were monitored at three different temperatures in a range ofdifferent water activities. Form 1 was present in most cases with noevidence of Form 2. From acetone and acetone:water (99:1) only Form 1was observed. Form 5 peaks were observed in mixture with Form 1 for theslurry in EtOAc:Water (99:1). Form 4 was observed from the samplesanalyzed from THF:Water (98:2). Only Form 1 was observed from EtOH:Water(95:5) and IPA:Water (94:6).

Finally, a new pattern was identified from ACN:Water (93:7), denoted asPattern 12. The material was later isolated by filtration andre-analyzed by XRPD. The sample maintained the same XRPD pattern,Pattern 12.

Example 15. X-Ray Powder Diffraction (XRPD) XX.1 Bruker AXS C2 GADDS

XRPD diffractograms were collected on a Bruker AXS C2 GADDSdiffractometer using Cu Kα radiation (40 kV, 40 mA), an automated XYZstage, a laser video microscope for auto-sample positioning and aVåntec-500 2-dimensional area detector. X-ray optics consists of asingle Gobel multilayer mirror coupled with a pinhole collimator of 0.3mm.

The beam divergence, i.e. the effective size of the X-ray beam on thesample, was approximately 4 mm. A θ-θ continuous scan mode was employedwith a sample—detector distance of 20 cm which gives an effective 2θrange of 1.5°-32.5°. Typically, the sample was exposed to the X-ray beamfor 120 seconds. The software used for data collection and analysis wasGADDS for Win7/XP and Diffrac Plus EVA respectively.

Samples run under ambient conditions (post VAC-XRPD) were analyzed asprepared for the vacuum experiment, using the sample retained within theAnton Parr metal recessed holder.

XX2 Bruker AXS D8 Advance

XRPD diffractograms were collected on a Bruker D8 diffractometer usingCu Kα radiation (40 kV, 40 mA) and a θ-2θ goniometer fitted with a Gemonochromator. The incident beam passes through a 2.0 mm divergence slitfollowed by a 0.2 mm antiscatter slit and knife edge. The diffractedbeam passes through an 8.0 mm receiving slit with 2.5° Soller slitsfollowed by the Lynxeye Detector. The software used for data collectionand analysis was Diffrac Plus XRD Commander and Diffrac Plus EVArespectively.

Samples were run under ambient conditions as flat plate specimens. Thesample was prepared on a polished, zero-background (510) silicon waferby gently pressing onto the flat surface or packed into a cut cavity.The sample was rotated in its own plane.

The details of the standard Pharmorphix data collection method are:

-   -   Angular range: 2 to 42° 2θ    -   Step size: 0.05° 2θ    -   Collection time: 0.5 s/step (total collection time: 6.40 min)

XX3 PANalytical Empyrean

XRPD diffractograms were collected on a PANalytical Empyreandiffractometer using Cu Kα radiation (45 kV, 40 mA) in transmissiongeometry. A 0.5° slit, 4 mm mask and 0.04 rad Soller slits with afocusing mirror were used on the incident beam. A PIXcel3D detector,placed on the diffracted beam, was fitted with a receiving slit and 0.04rad Soller slits. The software used for data collection was X'Pert DataCollector using X'Pert Operator Interface. The data were analyzed andpresented using Diffrac Plus EVA or HighScore Plus.

Samples were prepared and analyzed in either a metal or Millipore 96well-plate in transmission mode. X-ray transparent film was used betweenthe metal sheets on the metal well-plate and powders (approximately 1-2mg) were used as received. The Millipore plate was used to isolate andanalyze solids from suspensions by adding a small amount of suspensiondirectly to the plate before filtration under a light vacuum.

The scan mode for the metal plate used the gonio scan axis, whereas a 2θ scan was utilized for the Millipore plate.

The details of the standard screening data collection method are:

-   -   Angular range: 2.5 to 32.0° 20    -   Step size: 0.0130° 20    -   Collection time: 12.75 s/step (total collection time of 2.07        min)

Non-Ambient Conditions

XRPD diffractograms were collected on a PANalytical Empyreandiffractometer using Cu Kα radiation (45 kV, 40 mA) in reflectiongeometry. The instrument is fitted with an Anton Paar CHC plus+ stagefitted with graphite/Kapton windows and equipped with air cooling/andcoupled with a proUmid MHG32 Modular Humidity Generator, or a low vacuumpump system using an Edwards RV3 pump. A programmable divergence slit(in automatic mode), with a 10 mm fixed incident beam mask, Ni filterand 0.04 rad Soller slits were used on the incident beam. A PIXcel3Ddetector, placed on the diffracted beam, was fitted with a programmableantiscatter slit (in automatic mode) and 0.04 rad Soller slits.

The software used for data collection was X'Pert Data Collector and thedata analyzed and presented using Diffrac Plus EVA or Highscore Plus.

For vacuum (VAC-XRPD) experiments the sample was prepared and analyzedin an Anton Paar chromed sample holder. A reference XPRD pattern wascollected before applying the vacuum. Measurements were taken every 5min for 1.5 h then at 20 min intervals for 2 h, followed by hourlysampling for 3 h. The sample was left under vacuum for 72 h, a finalmeasurement taken and then the vacuum released. Further measurement(post vac) were collected every 10 mins for 3 h, exposing the sample toambient conditions. The measurement parameters are as per the standardscreening data collection method (detailed above).

For variable temperature (VT-XRPD) experiments the samples were preparedand analyzed in an Anton Paar chromed sample holder. A heating/coolingrate of 10° C./min was used with a 2 min isothermal hold before themeasurement started. The measurement parameters are as per the standardscreening data collection method (detailed above). Measurements weretaken at the following temperatures:

Target Temperature (° C.) 25 75 80 90 100 110 120 130 140 145 25

For variable humidity (VH-XRPD, Form 1) experiments the sample wasprepared and analyzed in an Anton Paar chromed sample holder. Themeasurement parameters are as per the standard screening data collectionmethod (detailed above). Measurements were taken at the followinghumidities:

Target RH/% Hold Duration 40 1 h 60 1 h 80 1 h 90 12.5 h   80 2 h 60 2 h40 2 h 20 2 h 10 12.5 h   20 2 h 40 2 h

Data collection occurs at start and end of each section, with 1 hsampling interval.

Characterization of Solid State Forms and Patterns of Compound II

The X-Ray powder diffraction pattern for crystalline Form 1 of CompoundII is displayed in FIG. 1 . The X-Ray powder diffraction pattern forcrystalline hydrate Form 2 of Compound II is displayed in FIG. 6 . TheX-Ray powder diffraction pattern for crystalline 2-methyltetrahydrofuransolvate Form 3 of Compound II is displayed in FIG. 9 . The X-Ray powderdiffraction pattern for crystalline tetrahydrofuran solvate Form 4 ofCompound II is displayed in FIG. 12 . The X-Ray powder diffractionpattern for crystalline acetone solvate Form 5 of Compound II isdisplayed in FIG. 15 . The X-Ray powder diffraction pattern forcrystalline hydrate Pattern 9 of Compound II is displayed in FIG. 18 .The X-Ray powder diffraction pattern for amorphous Compound II isdisplayed in FIG. 21 . The X-Ray powder diffraction pattern for pattern12 of Compound II is displayed in FIG. 24 .

Characterization of Crystalline Form 1 of Compound II

The X-Ray powder diffraction pattern for crystalline Form 1 of CompoundII is displayed in FIG. 1 . Characteristic peaks include the peakslisted in the following table:

Angle 2-Theta (°) Rel. Intensity (%) 2.8 100.0 6.7 17.0 7.2 22.6 13.424.2 17.8 23.5 19.7 24.6 19.9 25.6 20.6 22.9 21.8 23.7

Characterization of Crystalline Hydrate Form 2 of Compound II

The X-Ray powder diffraction pattern for crystalline hydrate Form 2 ofCompound II is displayed in FIG. 6 . Characteristic peaks include thepeaks listed in the following table:

Angle 2-Theta (°) Rel. Intensity (%) 4.5 100.0 13.8 42.5 17.6 65.3 18.348.8 19.0 64.2 19.6 55.2 19.9 68.4 20.5 62.9 23.0 52.5

Characterization of the Crystalline Tetrahydrofuran Solvate Form 4 ofCompound II

The X-Ray powder diffraction pattern for crystalline tetrahydrofuransolvate Form 4 of Compound II is displayed in FIG. 12 . Characteristicpeaks include the peaks listed in the following table:

Angle 2-Theta (°) Rel. Intensity (%) 3.3 100.0 5.7 16.3 11.9 14.4 19.815.2 20.1 42.4 20.7 23.2 22.9 17.1 23.1 15.6

Crystalline tetrahydrofuran solvate Form 4 of sodium(E)-2-(4-((3-(4-fluorophenyl)-3-(4-(3-morpholinoprop-1-yn-1-yl)phenyl)allyl)oxy)-2-methylphenoxy)acetatehas an unchanged XRPD after heating to 110° C.

Characterization of Crystalline Acetone Solvate Form 5 of Compound II

The X-Ray powder diffraction pattern for crystalline acetone solvateForm 5 of Compound II is displayed in FIG. 15 . Characteristic peaksinclude the peaks listed in the following table:

Angle 2-Theta (°) Rel. Intensity (%) 2.8 100.0 8.3 15.4 8.7 11.3 13.116.1 19.4 21.9 20.2 12.2 21.3 16.6 24.6 14.6

Example 16: Differential Scanning Calorimetry (DSC) XX.1 TA InstrumentsQ2000

DSC data were collected on a TA Instruments Q2000 equipped with a 50position auto-sampler. Typically, 0.5-3 mg of each sample, in apin-holed aluminum pan, was heated at 10° C./min from 25° C. to 275° C.A purge of dry nitrogen at 50 ml/min was maintained over the sample.

Modulated temperature DSC was carried out using an underlying heatingrate of 2° C./min and temperature modulation parameters of ±0.626° C.(amplitude) every 60 seconds (period).

The instrument control software was Advantage for Q Series and ThermalAdvantage and the data were analyzed using Universal Analysis or TRIOS.

XX2 TA Instruments Discovery DSC

DSC data were collected on a TA Instruments Discovery DSC equipped witha 50 position auto-sampler. Typically, 0.5-2 mg of each sample, in apin-holed aluminum pan, was heated at 10° C./min from 25° C. to 280° C.A purge of dry nitrogen at 50 ml/min was maintained over the sample.

The instrument control software was TRIOS and the data were analyzedusing TRIOS or Universal Analysis.

The DSC thermogram for crystalline Form 1 of Compound II is displayed inFIG. 2 . The DSC thermogram for crystalline hydrate Form 2 of CompoundII is displayed in FIG. 7 . The DSC thermogram for crystalline2-methyltetrahydrofuran solvate Form 3 of Compound II is displayed inFIG. 10 . The DSC thermogram for crystalline tetrahydrofuran solvateForm 4 of Compound II is displayed in FIG. 13 . The DSC thermogram forcrystalline acetone solvate Form 5 of Compound II is displayed in FIG.16 . The DSC thermogram for crystalline hydrate Pattern 9 of Compound IIis displayed in FIG. 19 . The DSC thermogram for amorphous Compound IIis displayed in FIG. 22 . The DSC thermogram for crystalline Pattern 12of Compound II is displayed in FIG. 25 .

Differential Scanning calorimetry (DSC) thermogram endotherms forselected forms and patterns are as described in the following table:

Solid State Form DSC Endotherms amorphous broad endotherm with onset at43.1° C. and peak at about 60.3° C., broad exotherm with onset at 107.0°C. and peak at 112.9° C.; and endotherm with onset at 125.0° C. peak a130.4° C. Form 1 onset at about 179.5° C. and peak at about 181.6° C.Form 2 six endothermic events: onset at about 44.1° C. and peak at about72.4° C.; peak at about 92.4° C.; onset at about 107.0° C. and peak atabout 118.5° C.; onset at about 127.6° C. and peak at about 130.0° C.;onset at about 146.9° C. and peak at about 149.9° C.; and onset at about179.5° C. and peak at about 181.1° C. Form 3 three endothermic events:onset at about 58.7° C. and peak at about 73.2° C.; onset at about114.5° C. and peak at about 136.2° C.; and onset at about 172.5° C. andpeak at about 178.6° C. Form 4 two endothermic events: onset at about111.7° C. and peak at about 114.5° C. with a broad shoulder starting atabout 70° C.; and onset at about 142.5° C. and peak at about 147.2° C.with a broad shoulder starting at about 130.6° C. Form 5 two endothermicevents having: an onset at 75.8° C. and two peaks at about 85.8° C. and97.2° C.; and onset at 180.4° C. and a peak at 182.2 Pattern 9 threeendothermic events: onset at about 38.5° C. and two peaks at about 71.5°C. and 94.1° C.; onset at about 107.1° C. and two peaks at about 118.0°C. and 130.0° C.; and onset at about 146.8° C. and peak at about 150.0°C. Pattern 5 four endothermic events: onset at about 50.7° C. and twopeaks at about 54.6° C. and 60.1° C.; onset at about 125.4° C. and peakat about 130.4° C.; onset at about 142.7° C. and peak at about 146.2°C.; and onset at about 172.4° C. and peak at about 181.0° C. Pattern 6three endothermic events: onset at about 88.0° C. and two peaks at about97.7° C. and 105.5° C.; onset at about 120.3° C. and four peaks at about125.1° C., 132.4° C., 134.7° C., and 144.2° C.; and onset at about176.5° C. and peak at about 180.3° C. Pattern 12 five endothermicevents: onset at about 54.7° C. and peak at about 81.5° C.; onset atabout 90.1° C. and peak at about 92.2° C.; onset at about 115.9° C. andpeak at about 124.6° C.; onset at about 131.3° C. and peak at about132.5° C.; and onset at about 146.8° C. and peak at about 150.6° C.

Example 17: Thermogravimetric Analysis (TGA) XX.1 TA Instruments Q500

TGA data were collected on a TA Instruments Q500 TGA, equipped with a 16position auto-sampler. Typically, 5-10 mg of each sample was loaded ontoa pre-tared aluminum DSC pan and heated at 10° C./min from ambienttemperature to 350° C. A nitrogen purge at 60 ml/min was maintained overthe sample.

The instrument control software was Advantage for Q Series and ThermalAdvantage and the data were analyzed using Universal Analysis.

The TGA pattern for crystalline Form 1 of Compound II is displayed inFIG. 3 . The TGA pattern for crystalline hydrate Form 2 of Compound IIis displayed in FIG. 8 . The TGA pattern for crystalline2-methyltetrahydrofuran solvate Form 3 of Compound II is displayed inFIG. 11 . The TGA pattern for crystalline tetrahydrofuran solvate Form 4of Compound II is displayed in FIG. 14 . The TGA pattern for crystallinehydrate Pattern 9 of Compound II is displayed in FIG. 20 . The TGApattern for amorphous Compound II is displayed in FIG. 23 .

Thermogravimetric Analysis (TGA) patterns for selected forms andpatterns are as described in the following table:

Solid State Form TGA Pattern amorphous 3.7% w/w loss from 25 to 150° C.,and a degradation onset at about 260° C. Form 1 0.1% w/w loss from 25 to60° C. and degradation onset at about 250° C. Form 2 17.2% w/w loss from25 to 145° C., and degradation onset at about 275° C. Form 3 2.3% w/wloss from 25 to 82° C., a further 3.8% w/w loss from 82° C. to 155° C.,and a degradation onset at about 275° C. Form 4 14.3% w/w loss from 25to 175° C., and degradation onset at about 285° C. Pattern 9 8.6 % w/wloss from 25 to 105° C., and degradation onset at about 270° C. 1.0% w/wloss from 25 to 51° C., a further 7.6% w/w loss from 51 to 91° C., aPattern 5 further 4.7% w/w loss from 91° C. to 156° C., and adegradation onset at about 275° C. Pattern 6 15.6% w/w loss from 25 to187° C., and a degradation onset at about 260° C.

Example 18: Gravimetric Vapor Sorption (GVS)

Sorption isotherms were obtained using a SMS DVS Intrinsic moisturesorption analyzer, controlled by DVS Intrinsic Control software. Thesample temperature was maintained at 25° C. by the instrument controls.The humidity was controlled by mixing streams of dry and wet nitrogen,with a total flow rate of 200 ml/min. The relative humidity was measuredby a calibrated Rotronic probe (dynamic range of 1.0-100% RH), locatednear the sample. The weight change, (mass relaxation) of the sample as afunction of % RH was constantly monitored by a microbalance (accuracy±0.005 mg).

Typically, 5-30 mg of sample was placed in a tared mesh stainless steelbasket under ambient conditions. The sample was loaded and unloaded at40% RH and 25° C. (typical room conditions). A moisture sorptionisotherm was performed as outlined below (2 scans per complete cycle).The standard isotherm was performed at 25° C. at 10% RH intervals over a0-90% RH range. Typically, a double cycle (4 scans) was carried out.Data analysis was carried out within Microsoft Excel using the DVSAnalysis Suite.

The method for SMS DVS Intrinsic experiments is outlined in thefollowing table:

Parameter Value Adsorption - Scan 1 (% RH) 40-90 Desorption,Adsorption - Scan 2 (% RH) 90-0, 0-40 Intervals (% RH) 10 Number ofScans 4 Flow rate (mL/min) 200 Temperature (° C.) 25 Stability (°C./min) 0.2 Sorption Time (hours) 6 hour time out Number of cycles 2

Reversible water uptake for the crystalline forms and patterns asdetermined by Gravimetric Vapor Sorption (GVS) are as described in thefollowing table:

Solid State Form Reversible Water Uptake between 0-90% RH Form 1 ~13.0%† Form 2 ~25% Form 4 ~23% Form 5 ~11% Pattern 9 ~27% Form 3 ~9.0%  † GVSdata for Form 1 can vary from batch to batch of synthesis

The samples were recovered after completion of the isotherm experimentat 90% RH and 25° C. and re-analyzed by XRPD. Results of the subsequentXRPD analysis are described in the following table:

Solid State Form Before GVS Solid State Form After GVS Form 1 Unchanged(Form 1) Form 2 Unchanged (Form 2) Form 4 Form 2 Form 5 Form 1 Pattern 9Unchanged (Pattern 9) Form 3 Form 1

Example 19: Stability of Solid State Forms

Samples were assessed for stability under ambient or static storageconditions of 25° C./97% RH and 40° C./75% RH for 7 or 10 days. Thesamples were then re-analyzed by XRPD.

Results of the subsequent XRPD analysis for the crystalline forms aredescribed in the following table:

Solid State Form 25° C./97% RH/7 days 40° C./75% RH/7 days Form 1 Form 2Unchanged (Form 1) Form 2 Unchanged (Form 2) Unchanged (Form 2) Form 4Form 2 Form 1 Pattern 9 some changes: similar some changes: to patternsimilar to pattern 9 9 and Form 2 and Form 2 Form 3 — Form 1

There was no change in the XRPD of the amorphous solid form underambient storage conditions for 24 hours, 48 hours, 7 days, or 10 days.There was no change in the XRPD of the amorphous solid form under staticstorage of 40° C./75% RH for 10 days.

Example 20: High-Performance Liquid Chromatography (HPLC) Methods

Purity analysis was performed on an Agilent HP1100 series system (orequivalent) equipped with a diode array detector and using ChemStationsoftware. The full method details are provided below:

Parameter Value Type of method Reverse phase with gradient elutionSample Preparation 0.25 mg/mL in acetonitrile:water 1:1 Column SupelcoAscentis Express C18, 100 × 4.6 mm, 2.7 μm Column 25 Temperature (° C.)Injection (μL) 5 Wavelength, 255, 90 Bandwidth (nm) Flow Rate (mL/min) 2Phase A 0.1% TFA in water Phase B 0.085% TFA in acetonitrile TimetableTime (mm) % Phase A % Phase B 0 95 5 6 5 95 6.2 95 5 8 95 5

Parameter Value Type of method Reverse phase with gradient elutionSample Preparation 0.25 mg/mL in acetonitrile:water 1:1 Column SupelcoAscentis Express C18, 100 × 4.6 mm, 2.7 μm Column Temperature (° C.) 25Injection (μL) 5 Wavelength, Bandwidth (nm) 255, 90 Flow Rate (mL/min) 2Phase A 0.1% TFA in water Phase B 0.085% TFA in acetonitrile TimetableTime (min) % Phase A % Phase B 0 95 5 25 5 95 25.2 95 5 30 95 5

Parameter Value Type of method Reverse phase with gradient elutionSample Preparation 0.2 mg/mL in acetonitrile:water 1:1 Column HichromRPB C18, 250 × 4.6 mm, 5 μm Column Temperature (° C.) 35 Injection (μL)20 Wavelength, Bandwidth 248 (4)  (nm): (detection) Wavelength,Bandwidth 400 (100) (nm): (reference) Flow Rate (mL/min) 1.0 Aqueousbuffer 0.1M Ammonium Dihydrogen Phosphate, pH 2.5 Phase A 60:40 (Aqueousbuffer:ACN) Phase B 30:70 (Aqueous buffer:ACN) Timetable Time (min) %Phase A % Phase B 0.0 100.0 0.0 10.0 100.0 0.0 27.0 66.5 33.5 39.0 0.0100.0 40.0 100.0 0.0 50.0 100.0 0.0

Purity analysis of the different solid state forms indicated >99% purityof all forms. HPLC purity values are detailed in the table below:

Solid State Form HPLC Purity amorphous 99.5% (50 min method) Form 199.6% (50 min method) Form 2 99.3% (8 min method)  Form 3 99.5% (8 minmethod)  Form 4 99.6% (8 min method)  Pattern 9 99.7% (8 min method) Pattern 5 99.6% (8 min method)  Pattern 6 99.1% (8 min method) 

Example 21: Karl Fisher (KF) Titration

The water content of each sample was measured on a Metrohm 874 OvenSample Processor up to 150° C. with 851 Titrano Coulometer usingHydranal Coulomat AG oven reagent and nitrogen purge. Weighed solidsamples were introduced into a sealed sample vial. Approximately 10 mgof sample was used per titration and duplicate determinations were made.An average of these results is presented unless otherwise stated. Datacollection and analysis were performed using Tiamo software.

Results of the KF analysis for the crystalline forms are described inthe following table:

Solid State Form KF Form 1 0.7 wt % water (0.21 mol equiv) Form 2 19.1wt % water (150° C.) (7 mol equiv) Pattern 9 1.7 wt %/2.3 wt % water(100° C.) ( ~0.6 mol equiv) Form 3 0.5 wt % water (160° C.) (0.15 molequiv) amorphous 3.0 wt % water (0.92 mol equiv)

Example 22: Ion Chromatography

Data were collected on a Metrohm 930 Compact IC Flex with 858Professional autosampler and 800 Dosino dosage unit monitor, using ICMagicNet software. Accurately weighed samples were prepared as stocksolutions in a suitable solvent. Quantification was achieved bycomparison with standard solutions of known concentration of the ionbeing analyzed. Analyzes were performed in duplicate and an average ofthe values is given unless otherwise stated.

IC Method for Cation Chromatography Parameter Value Type of methodCation exchange Column Metrosep C 4 - 250 (4.0 × 250 mm) ColumnTemperature (° C.) Ambient Injection (μL) Various Detection Conductivitydetector Flow Rate (mL/min) 0.9 Eluent 1.7 mM Nitric Acid 0.7 mMDipicolinic acid in a 5% acetone aqueous solution.

IC Method for Anion Chromatography Parameter Value Type of method Anionexchange Column Metrosep A Supp 5 - 150 (4.0 × 150 mm) ColumnTemperature (° C.) Ambient Injection (μL) Various Detection Conductivitydetector Flow Rate (mL/min) 0.7 Eluent 3.2 mM sodium carbonate, 1.0 mMsodium hydrogen carbonate in a 5% acetone aqueous solution.

Ion chromatography of the crystalline Form 1 of Compound II indicated1.1 mol equivalents of sodium (adjusted for water), with no other anionsor cations present.

Ion chromatography of the crystalline 2-methyltetrahydrofuran solvateForm 3 of Compound II indicated 0.96 mol equivalents of sodium (adjustedfor water), with no other anions or cations present.

Ion chromatography of the crystalline tetrahydrofuran solvate Form 4 ofCompound II indicated 1.01 mol equivalents of sodium (adjusted forwater), with no other anions or cations present.

Example 23: Fourier Transform Infrared (FTIR) Spectroscopy

Data were collected on a Perkin-Elmer Spectrum One fitted with auniversal Attenuated Total Reflectance (ATR) sampling accessory from4000-650 cm⁻¹ over 16 scans. The data were collected using Spectrumsoftware and processed using ACD Spectrus Processor.

Characterization of Crystalline Form 1 of Compound II

The Fourier Transform Infrared (FTIR) spectrum for crystalline Form 1 ofCompound II is shown in FIG. 4 . Characteristic peaks include peaks at810 cm⁻¹, 838 cm⁻¹, 1220 cm⁻¹, 1504 cm⁻¹, and 1612 cm⁻¹. Additionalcharacteristic peaks are listed in the following table:

Wavelength (cm⁻¹) Rel. Intensity* 798 M 810 S 838 S 864 M 1009 M 1035 M1043 M 1052 M 1115 S 1160 M 1220 VS 1236 M 1333 M 1413 M 1425 M 1504 S1612 VS *M = medium; S = strong; VS = very strong

Characterization of Crystalline Acetone Solvate Form 5 of Compound II

The Fourier Transform Infrared (FTIR) spectrum for crystalline acetonesolvate Form 5 of Compound II is shown in FIG. 17 . Characteristic peaksinclude peaks at 810 cm⁻¹, 838 cm⁻¹, 1220 cm⁻¹, 1504 cm⁻¹, and 1612cm⁻¹. Additional characteristic peaks are listed in the following table:

Wavelength (cm⁻¹) Rel. Intensity* 798 M 810 S 838 S 864 M 1009 M 1042 M1053 M 1116 M 1160 M 1220 VS 1236 M 1333 M 1412 M 1424 M 1504 S 1612 VS*M = medium; S = strong; VS = very strong

Example 24: Raman Spectroscopy

Data were collected on a Renishaw inVia Qontor. Instrument control, dataanalysis and presentation software was WiRE.

-   -   Method: excitation source, λ_(ex)=785 nm laser, attenuated        appropriately to avoid sample degradation    -   Raman shift range: 100-3200 cm⁻¹    -   Exposure time: 10 s    -   Accumulations: 1

Characterization of Crystalline Form 1 of Compound II

The Raman spectrum for crystalline Form 1 of Compound II is shown inFIG. 5 . Characteristic peaks are listed in the following table:

Wavelength (cm⁻¹) Rel. Intensity* 103 M 126 M 810 M 1158 M 1238 M 1604VS 1629 M * M = medium; S = strong; VS = very strong

Example 25: Single Crystal X-Ray Diffraction (SCXRD) Preparation ofSingle Crystal

A crystal of Compound II (Form 1) was isolated from an aggregate ofcrystals obtained by evaporation from an EtOAc/H₂O (99:1 v/v %)solution. The approximate dimensions of the crystal were:0.40×0.03×0.005 mm.

Collection and Characterization

Data were collected on a Rigaku Oxford Diffraction Supernova DualSource, Cu at Zero, Atlas CCD diffractometer equipped with an OxfordCryosystems Cobra cooling device. The data were collected using Cu Kαradiation (λ=1.5418 Å) at a constant temperature with w variable scantechnique (2.807 to 50.989° 0). Additional collection and refinementparameters are outlined in Table 1, below.

Structures were solved and refined using the Bruker AXS SHELXTL suite orthe OLEX² crystallographic software. Unless otherwise stated, hydrogenatoms attached to carbon were placed geometrically and allowed to refinewith a riding isotropic displacement parameter. Hydrogen atoms attachedto a heteroatom were located in a difference Fourier synthesis and wereallowed to refine freely with an isotropic displacement parameter. Areference diffractogram for the crystal structure was generated inMercury.

TABLE 1 Data collection and structure refinement for Compound II(Form 1) Diffractometer SuperNova, Dual, Cu at zero, Atlas Radiationsource SuperNova (Cu) X-ray Source, CuKα Data collection method omegascans Theta range for data collection 2.807 to 50.989° Index ranges −31≤ h ≤ 31, −6 ≤ k < 5, −27 ≤ 1 ≤ 27 Reflections collected 28094Independent reflections 5555 [R(int) = 0.1913] Coverage of independentreflections 58.4% Variation in check reflections n/a Absorptioncorrection Multi-scan Max. and min. transmission 1.00000 and 0.42918Structure solution technique Direct Methods Structure solution programSHELXTL (Sheldrick, 2013) Refinement technique Full-matrix least-squareson F² Refinement program SHELXL-2014/6 (Sheldrick, 2014) Functionminimised Σ w(F_(o) ² − F_(c) ²)² Data/restraints/parameters 5555/0/705Goodness-of-fit on F² 1.007 Δ/σ_(max) 0.000 Final R indices: R1 =0.0945, wR2 = 0.2099 2657 data; I > 2σ(I) R1 = 0.1886, wR2 = 0.2771 alldata Weighting scheme w = 1/[σ² (F_(o) ²) + 0.1224P)²] where P = (F_(o)² + 2F_(c) ²)/3 Extinction coefficient n/a Largest diff. peak and hole0.426 and −0.390 eÅ⁻³

Refinement summary:

Ordered Non-H atoms, XYZ Freely refining Ordered Non-H atoms, UAnisotropic H atoms (on carbon), XYZ Idealized positions riding H atoms(on carbon), U Appropriate multiple H atoms (on heteroatoms), XYZ Freelyrefined H atoms (on heteroatoms), U Isotropic Disordered atoms, OCC NoDisorder Disordered atoms, XYZ No Disorder Disordered atoms, U NoDisorder

The crystal structure of Compound II (Form 1) was determined at 100 Kand a summary of the structural data can be found in Tables 2, 3, and 4.The X-ray data were collected up to 1.0 Å resolution, using exposures of100 seconds per frame at the low θ-angle and 200 seconds per frame atthe higher θ-angle. At certain crystal orientations, the diffractionpattern shows split and streaky reflections which reflects the overallcrystal quality and could indicate potential twinning.

The crystals are monoclinic, space group P2/c and refined with a finalR1 [I>2σ(I)] value of 9.45%. Platon ADDSYM analysis was performed and noadditional space group was found. Moreover, the structure solution wasalso attempted in the more common P2₁/c space group, however, nosatisfactory structure solution was found. Despite only low resolutiondata being collected for this crystal structure, the data was sufficientto successfully determine the crystal structure of Compound II (Form 1)in P2/c space group and confirm the atomic connectivity which isconsistent with the molecular 2D representation. The asymmetric unitcontains two fully ordered Compound I anions and two independent Na⁺cations.

TABLE 2 Crystal Data of Compound II (Form 1) at 100 K Crystal SystemMonoclinic Space Group P2/c a (Å) 31.581(3) b (Å) 6.1180(4) c (Å)27.2046(18) α 90° β 94.447(7)° γ 90° V (Å³) 5240.4(7) Z 8 CalculatedDensity (Mg/m³) 1.363 Absorption coefficient (mm⁻¹) 0.937 F(000) 2256

TABLE 3 Fractional Atomic Coordinates for Compound II (Form 1) at 100 Kx/a y/b z/c Na1A 0.55177(12) 0.7521(5) 0.27685(13) F1A 0.11468(18)0.1067(9) 0.5137(2) O1A 0.5084(2) 1.6234(10) 0.3364(2) O2A 0.4711(2)1.9101(10) 0.3072(2) O3A 0.4420(2) 1.4498(10) 0.3786(2) O4A 0.3042(2)0.9658(10) 0.4278(2) O5A −0.0492(2) 0.8045(12) 0.1069(3) N1A 0.0218(3)1.0358(13) 0.1493(3) C1A 0.4750(3) 1.7319(17) 0.3316(3) C2A 0.4347(3)1.6488(15) 0.3518(3) C3A 0.4054(3) 1.3482(16) 0.3910(3) C4A 0.3645(3)1.4107(15) 0.3761(3) CSA 0.3295(3) 1.2894(15) 0.3868(3) C6A 0.3358(3)1.0998(17) 0.4152(3) C7A 0.3763(3) 1.0428(14) 0.4321(3) C8A 0.4120(3)1.1565(16) 0.4210(3) C9A 0.4557(3) 1.0922(15) 0.4400(3) C10A 0.2618(3)1.0346(15) 0.4183(4) C11A 0.2352(3) 0.8655(16) 0.4405(3) C12A 0.1986(3)0.7796(15) 0.4212(3) C13A 0.1766(3) 0.6035(14) 0.4464(3) C14A 0.1990(3)0.4644(16) 0.4787(3) C15A 0.1781(3) 0.2962(16) 0.5027(3) C16A 0.1358(4)0.2724(16) 0.4913(3) C17A 0.1116(3) 0.4139(16) 0.4608(3) C18A 0.1326(4)0.5764(16) 0.4386(4) C19A 0.1763(3) 0.8646(16) 0.3748(3) C20A 0.1673(3)0.7262(15) 0.3345(4) C21A 0.1426(3) 0.7969(16) 0.2942(4) C22A 0.1250(3)1.0087(18) 0.2925(4) C23A 0.1354(3) 1.1487(16) 0.3320(4) C24A 0.1600(3)1.0762(16) 0.3715(4) C25A 0.0966(4) 1.0763(16) 0.2511(4) C26A 0.0724(3)1.1350(17) 0.2182(4) C27A 0.0403(3) 1.2154(16) 0.1803(4) C28A −0.0023(3)0.8873(15) 0.1787(4) C29A −0.0221(4) 0.7113(18) 0.1459(4) C30A−0.0269(4) 0.9488(18) 0.0779(4) C31A −0.0076(3) 1.1299(15) 0.1108(4)Na1B 0.50100(12) 1.2565(5) 0.32498(12) F1B 0.94656(18) 0.5969(8)0.4452(2) O1B 0.5610(2) 1.1172(9) 0.2949(2) O2B 0.5623(2) 1.3963(11)0.2415(2) O3B 0.6224(2) 0.9057(10) 0.2598(2) O4B 0.7554(2) 0.3890(10)0.2088(2) O5B 0.5490(2) −0.7247(10) 0.4023(2) N1B 0.6179(3) −0.6391(12)0.4735(3) C1B 0.5754(4) 1.2146(19) 0.2598(4) C2B 0.6129(3) 1.1120(15)0.2360(4) C3B 0.6584(3) 0.7925(15) 0.2471(3) C4B 0.6805(3) 0.8379(16)0.2073(4) CSB 0.7135(3) 0.7053(15) 0.1952(3) C6B 0.7243(3) 0.5240(16)0.2248(4) C7B 0.7029(3) 0.4838(14) 0.2653(3) C8B 0.6697(3) 0.6152(15)0.2783(3) C9B 0.6461(3) 0.5722(13) 0.3234(3) C10B 0.7719(3) 0.2156(14)0.2414(3) C11B 0.8036(3) 0.2993(14) 0.2795(4) C12B 0.8085(3) 0.2600(14)0.3285(3) C13B 0.8438(3) 0.3582(15) 0.3596(3) C14B 0.8624(3) 0.2370(14)0.3989(3) C15B 0.8962(3) 0.3143(16) 0.4279(4) C16B 0.9127(3) 0.5176(18)0.4166(4) C17B 0.8953(3) 0.6460(15) 0.3782(4) C18B 0.8614(3) 0.5608(16)0.3505(4) C19B 0.7785(3) 0.1160(17) 0.3530(4) C20B 0.7610(3) 0.1914(15)0.3965(4) C21B 0.7357(3) 0.0582(15) 0.4221(3) C22B 0.7278(3) −0.1574(16)0.4069(4) C23B 0.7446(3) −0.2323(13) 0.3643(3) C24B 0.7692(3)−0.0950(15) 0.3375(3) C25B 0.7035(3) −0.3033(16) 0.4361(3) C26B0.6837(3) −0.4190(15) 0.4608(3) C27B 0.6583(3) −0.5563(14) 0.4930(3)C28B 0.5892(3) −0.4684(15) 0.4538(3) C29B 0.5462(3) −0.5614(16)0.4400(4) C30B 0.5779(3) −0.8945(15) 0.4192(4) C31B 0.6209(3)−0.8071(14) 0.4349(3)

TABLE 4 Hydrogen Atom Coordinates for Compound II (Form 1) at 100 K x/ay/b z/c H2AA 0.4236 1.7608 0.3738 H2AB 0.4129 1.6239 0.3242 H4A 0.36021.5421 0.3577 H5A 0.3017 1.3339 0.3751 H 0.3799 0.9176 0.4526 H9AA 0.4671.2009 0.464 H9AB 0.474 1.0846 0.4125 HA 0.4548 0.9488 0.4559 H10A0.2543 1.0456 0.3823 H10B 0.2574 1.1792 0.4334 H11A 0.2453 0.8126 0.4721H14A 0.2288 0.482 0.4848 H15A 0.1931 0.2031 0.526 H17A 0.0817 0.3980.4556 H18A 0.1169 0.6743 0.4171 H20A 0.1785 0.5819 0.3351 H21A 0.13720.7016 0.2668 H23A 0.1251 1.2947 0.3312 H24A 0.1664 1.1738 0.3982 H27A0.0535 1.3232 0.1592 H27B 0.0174 1.2905 0.1966 H28A −0.0248 0.96940.1943 HB 0.0168 0.8208 0.2052 HC 0.0005 0.6246 0.1319 H29B −0.03880.6118 0.1656 H30A −0.0465 1.0122 0.0515 H30B −0.0042 0.8691 0.0622 H31A0.0077 1.2344 0.0908 H31B −0.0305 1.2103 0.126 H2BA 0.6055 1.0894 0.2003H2BB 0.6379 1.2097 0.24 H4B 0.6731 0.9624 0.1875 H5B 0.7286 0.73680.1672 H7B 0.711 0.3617 0.2855 H9BA 0.6446 0.7071 0.3426 H9BB 0.6610.4595 0.3436 H9BC 0.6172 0.522 0.3133 H10C 0.7851 0.1016 0.2218 H10D0.7481 0.1474 0.2576 H11B 0.824 0.3966 0.2677 H14B 0.8512 0.097 0.4057H15B 0.9083 0.2316 0.455 H17B 0.9064 0.7862 0.3715 H18B 0.8491 0.64450.3236 H20B 0.7669 0.3358 0.4079 H21B 0.7235 0.1126 0.4505 H23B 0.7393−0.378 0.3535 H24B 0.7798 −0.147 0.3079 H27C 0.6761 −0.6831 0.5041 H27D0.6535 −0.4694 0.5228 H28C 0.6006 −0.4018 0.4244 H28D 0.5869 −0.35250.4788 H29C 0.5347 −0.6278 0.4693 H29D 0.5267 −0.4435 0.4277 H30C 0.5803−1.0023 0.3924 H30D 0.5664 −0.9711 0.4473 H31C 0.6395 −0.9277 0.4478H31D 0.6337 −0.7425 0.4062

The simulated XRPD pattern of Compound II (Form 1) at 100 K is shown inFIG. 26 .

An overlay with the experimental diffractogram at RT confirms that thesimulated diffractogram from the single crystal structure is consistentwith the experimental Compound II (Form 1) diffractogram (FIG. 27 ).

Example A-1: Parenteral Pharmaceutical Composition

To prepare a parenteral pharmaceutical composition suitable foradministration by injection (subcutaneous, intravenous), 1-100 mg of awater-soluble salt of a compound Formula (I), or a pharmaceuticallyacceptable salt or solvate thereof, is dissolved in sterile water andthen mixed with 10 mL of 0.9% sterile saline. A suitable buffer isoptionally added as well as optional acid or base to adjust the pH. Themixture is incorporated into a dosage unit form suitable foradministration by injection

Example A-2: Oral Solution

To prepare a pharmaceutical composition for oral delivery, a sufficientamount of a compound disclosed herein, or a pharmaceutically acceptablesalt thereof, is added to water (with optional solubilizer(s), optionalbuffer(s) and taste masking excipients) to provide a 20 mg/mL solution.

Example A-3: Oral Tablet

A tablet is prepared by mixing 20-50% by weight of a compound disclosedherein, or a pharmaceutically acceptable salt thereof, 20-50% by weightof microcrystalline cellulose, 1-10% by weight of low-substitutedhydroxypropyl cellulose, and 1-10% by weight of magnesium stearate orother appropriate excipients. Tablets are prepared by directcompression. The total weight of the compressed tablets is maintained at100-500 mg.

Example A-4: Oral Capsule

To prepare a pharmaceutical composition for oral delivery, 10-500 mg ofa compound disclosed herein, or a pharmaceutically acceptable saltthereof, is optionally mixed with starch or other suitable powderblends. The mixture is incorporated into an oral dosage unit such as ahard gelatin capsule, which is suitable for oral administration.

In another embodiment, 10-500 mg of a compound disclosed herein, or apharmaceutically acceptable salt thereof, is placed into Size 4 capsule,or size 1 capsule (hypromellose or hard gelatin) and the capsule isclosed.

The examples and embodiments described herein are for illustrativepurposes only and various modifications or changes suggested to personsskilled in the art are to be included within the spirit and purview ofthis application and scope of the appended claims.

1-56. (canceled)
 57. Crystalline sodium (E)-2-(4-((3-(4-fluorophenyl)-3-(4-(3-morpholinoprop-1-yn-1-yl)phenyl)allyl)oxy)-2-methylphenoxy)acetate (Compound II) that is characterized as having: an XRPD pattern substantially the same as shown in FIG. 24 ; a DSC thermogram substantially the same as shown in FIG. 25 ; a DSC thermogram with five endothermic events having: i. an onset at about 54.7° C. and peak at about 81.5° C.; ii. an onset at about 90.1° C. and peak at about 92.2° C.; iii. an onset at about 115.9° C. and peak at about 124.6° C.; iv. an onset at about 131.3° C. and peak at about 132.5° C.; and v. an onset at about 146.8° C. and peak at about 150.6° C.; or combinations thereof.
 58. A pharmaceutical composition comprising the crystalline Compound II of claim 57 and at least one pharmaceutically acceptable excipient.
 59. The pharmaceutical composition of claim 58, wherein the pharmaceutical composition is formulated for administration to a mammal by oral administration.
 60. The pharmaceutical composition of claim 58, wherein the pharmaceutical composition is in the form of a solid form pharmaceutical composition.
 61. The pharmaceutical composition of claim 60, wherein the pharmaceutical composition is in the form of a tablet, a pill, or a capsule; and wherein the pharmaceutical composition comprises about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, or about 400 mg of crystalline Compound II.
 62. Amorphous sodium (E)-2-(4-((3-(4-fluorophenyl)-3-(4-(3-morpholinoprop-1-yn-1-yl)phenyl)allyl)oxy)-2-methylphenoxy)acetate (Compound II) that is characterized as having: an XRPD pattern showing a lack of crystallinity; a DSC thermogram substantially the same as shown in FIG. 22 ; a DSC thermogram with: i. a broad endotherm with onset at 43.1° C. and peak at about 60.3° C.; ii. a broad exotherm with onset at 107.0° C. and peak at 112.9° C.; and iii. an endotherm with onset at 125.0° C. peak a 130.4° C.; a TGA pattern substantially the same as shown in FIG. 23 ; a TGA pattern with a 3.7% w/w loss from 25 to 150° C., and a degradation onset at about 260° C.; an unchanged XRPD after storage at ambient temperature over 24 hours, 48 hours, 7 days, or 10 days; an unchanged XRPD after storage at 75% RH and 40° C. over 10 days; or combinations thereof.
 63. A pharmaceutical composition comprising the amorphous Compound II of claim 62 and at least one pharmaceutically acceptable excipient.
 64. The pharmaceutical composition of claim 63, wherein the pharmaceutical composition is formulated for administration to a mammal by oral administration.
 65. The pharmaceutical composition of claim 63, wherein the pharmaceutical composition is formulated for administration to a mammal by oral administration in the form of a tablet, a pill, a capsule, a suspension, or a solution.
 66. The pharmaceutical composition of claim 63, wherein the pharmaceutical composition is in the form of a solid form pharmaceutical composition.
 67. The pharmaceutical composition of claim 66, wherein the pharmaceutical composition is in the form of a tablet, a pill, or a capsule; and wherein the pharmaceutical composition comprises about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, or about 400 mg of crystalline Compound II.
 68. A process for the preparation of crystalline Compound II:

comprising adding sodium hydroxide in water to an acetone solution of Compound I:

or the alkyl ester of Compound I, or a salt thereof:

wherein R is C₁-C₆ alkyl; filtering the reaction mixture and adding the filtered reaction mixture to acetonitrile; filtering the crystalline Compound II that is formed from the solution; and filtering drying the solids to provide crystalline Compound II.
 69. The process of claim 68, wherein the crystalline Compound II is characterized as having an X-ray powder diffraction (XRPD) pattern with peaks at about 2.8° 2-Theta, about 7.2° 2-Theta, about 13.4° 2-Theta, about 17.8° 2-Theta, about 19.7° 2-Theta, about 19.9° 2-Theta, and about 20.6° 2-Theta as measured using Cu Kα radiation.
 70. The process of claim 68, wherein the filtered reaction mixture is added to acetonitrile that is seeded with crystalline Compound II that is characterized as having an X-ray powder diffraction (XRPD) pattern with peaks at about 2.8° 2-Theta, about 7.2° 2-Theta, about 13.4° 2-Theta, about 17.8° 2-Theta, about 19.7° 2-Theta, about 19.9° 2-Theta, and about 20.6° 2-Theta as measured using Cu Kα radiation.
 71. The process of claim 68, wherein the process comprises adding sodium hydroxide in water to an acetone solution of Compound I; filtering the reaction mixture and adding the filtered reaction mixture to acetonitrile comprising seeds of the crystalline Compound II; and filtering the crystalline Compound II that is formed from the solution; wherein the crystalline Compound II is characterized as having an X-ray powder diffraction (XRPD) pattern with peaks at about 2.8° 2-Theta, about 7.2° 2-Theta, about 13.4° 2-Theta, about 17.8° 2-Theta, about 19.7° 2-Theta, about 19.9° 2-Theta, and about 20.6° 2-Theta as measured using Cu Kα radiation. 